Search PubMed⌕ Search

Biomedical subjects

M Hoffman

Publications and source records attributed to M Hoffman.

At least 181 records · Page 10Linked to original sources
PubMed1994

Description of a second microsatellite marker and linkage analysis of the muscle glycogen synthase locus in familial NIDDM.

Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by impaired insulin-stimulated glucose uptake into glycogen. Both biochemical and genetic data have implicated glycogen synthase as a candidate for the genetic predisposition to diabetes. To test this hypothesis, we isolated cosmid clones containing genomic DNA for the glycogen synthase (GSY) gene and identified a region of 20 GT repeat units in a clone that extended 15 kilobases 3' to the gene. This region was highly polymorphic with nine alleles (heterozygosity 0.74). With the use of this polymorphism, the GSY was mapped on chromosome 19q between markers D19S217 and D19S210 and at theta = 0.036 from the histidine-rich calcium-binding protein (HRC) locus. Linkage to GSY was rejected under multiple models with logarithm of odds (LOD) scores of -1.36 to -5.22. In contrast, we could not reject linkage under dominant and intermediate (additive) models for the HRC locus (maximum LOD scores 1.51 and 1.54), despite the close proximity to GSY. Multipoint analysis of NIDDM versus GSY and HRC placed the putative diabetes locus centromeric to HRC and away from GSY. Furthermore, analysis of the previously associated Xba I polymorphism suggested neither linkage nor sib-pair sharing. We conclude that mutations of the GSY gene are unlikely to play a major role in the predisposition to NIDDM in our families. However, we cannot exclude a modifying role in a polygenic disorder or an important role in some families. The moderately positive LOD scores near the HRC locus suggest a need for evaluation of this region in additional NIDDM families.

Base Sequence↗
PubMed1994

Impaired interferon alpha response in hairy cell leukemia is corrected by therapy with 2-chloro-2'-deoxyadenosine: implications for susceptibility to opportunistic infections.

Patients with hairy cell leukemia (HCL) are susceptible to opportunistic intracellular infections, suggesting defects in cellular immunity. Prior studies have indicated an association between failure of IFN-alpha generation by peripheral blood mononuclear cells (MNC) and susceptibility to such infections. We here present results on IFN-alpha generation in HCL patients pre- and post-therapy. Prior to treatment with 2-chloro-2'-deoxyadenosine (CdA), MNC from 24 HCL patients with active disease produced little or not IFN-alpha (geometric mean < 40 IU/ml) compared with controls (n = 140, geometric mean 1730 IU/ml, p < 0.0005). After treatment with CdA, IFN-alpha generation was studied in 16 patients, with a geometric mean value of 650 IU/ml (p < 0.0005 compared with pre-CdA levels). The severe depression of IFN-alpha generation improved progressively following CdA therapy-induced clinical remission. We propose that deficiency of IFN-alpha production may play a role in the susceptibility to intracellular infections of patients with active HCL.

Adult↗
PubMed1994

Surgical and psychosexual outcome following vaginal reconstruction with pelvic exenteration.

The improved prognosis with pelvic exenterative surgery for gynecologic malignancies has resulted in increasing concern for quality of life. Sexual dysfunction is a common sequel to pelvic exenteration and vaginal reconstruction should be considered in all these patients. This case review assesses our experience with three flap techniques for neovaginal construction. Medical charts were reviewed and survivors interviewed. Fourteen patients had vaginal reconstruction with gracilis myocutaneous (n. = 5), bulbocavernosus (n. = 3) or pudendal thigh fasciocutaneous (n. = 6) flaps at the time of pelvic exenteration. Partial or incomplete necrosis occurred in four (24%) and one (7%) patient had complete flap necrosis bilaterally, followed by an entero-vaginal fistula. Two patients developed recto-vaginal fistula in association with a low rectal reanastomosis (n. = 2) and tumor recurrence (n. = 1). Eight patients, seven of whom agreed to an interview and physical examination, are alive at a median of 15.5 months following pelvic exenteration. Three have stenotic and/or foreshortened vaginas. Two patients are apareunic by choice, four have discontinued vaginal intercourse because of dyspareunia and only one patient has satisfactory coitus. Other problems include vulvar pain (n. = 3), vaginal discharge (n. = 3), neovaginal hair growth (n. = 5) and protrusion of flaps (n. = 3). The functional results in this series are disappointing and better methods of vaginal reconstruction should continue to be developed. Patients undergoing neovaginal reconstruction at the time of pelvic exenteration require careful preoperative counselling and ongoing support after surgery with special attention to sexual dysfunction.

Adult↗
PubMed1993

[Absence of mitral valve prolapse during panic attacks induced by sodium lactate].

The recent identification of a new type of anxiety state, panic attack, has drawn attention to common pathways between panic disorder and cardiac somatization, particularly mitral valve collapse. A double-blind study was set up, using doppler-echocardiography during a panic attack induced by sodium lactate infusion. The results showed that there was no relationship between panic attack and mitral valve collapse, and that the lactate infusion-anxiety rate was only 35 percent.

Adolescent↗
PubMed1993

Enhanced immunity to human immunodeficiency virus (HIV) envelope elicited by a combined vaccine regimen consisting of priming with a vaccinia recombinant expressing HIV envelope and boosting with gp160 protein.

Transmission studies have suggested that an optimal human immunodeficiency virus type 1 (HIV-1) vaccine should induce both neutralizing antibodies and cytolytic T cells to eliminate free virus and infected cells. A phase I trial in healthy HIV-1-seronegative persons was conducted with a combination HIV-1 vaccine regimen (strain IIIB) consisting of priming with a recombinant vaccinia (vac/env) virus expressing HIV-1 envelope and boosting with a gp160 glycoprotein derived from a recombinant baculovirus (rgp160). T-cell and antibody responses detected after immunization with either vac/env alone or rgp160 alone were generally of low magnitude and transient, and no subject developed neutralizing antibodies. In contrast, recipients of the combination regimen demonstrated in vitro T-cell proliferative responses to homologous HIV-1 antigens that were 3- to 10-fold higher than responses with either vaccine alone, and these responses were sustained for > 18 months in 75% of recipients. Moreover, both CD8+ and CD4+ cytolytic T cells were detected. Antibody responses (titer, 1:800 to 1:102,400) to homologous HIV envelope developed in all recipients of the combination regimen, and neutralizing antibodies were detected in 7 of 13. Thus, immunization with a live virus vaccine followed by boosting with a soluble protein offers promise for inducing the broad immunity needed in an HIV vaccine.

Baculoviridae↗
PubMed1993

Primary in vivo responses to ovalbumin. Probing the predictive value of the Kb binding motif.

CD8+ cytolytic T cells recognize Ag presented by MHC class I molecules on the surface of target cells. It is known that presenting cells process nascent protein into peptides of approximately eight to nine amino acids which bind to the peptide groove of MHC class I and are transported to the cell surface. Recently, several laboratories have postulated that each MHC class I haplotype has a binding motif of at least two amino acids nested within the peptide. One such motif is XXXXF/YXXL which binds to the mouse MHC class I molecule, H2-Kb, and can be found in the known antigenic peptide from OVA at amino acids 257-264. By using the motif to scan OVA five peptides were found that fit this pattern, OVA 11-18, OVA 55-62, OVA 107-114, OVA 176-183, and OVA 257-264. Binding studies revealed that three out of the five peptides (OVA 55-62, OVA 176-183, and OVA 257-264) bind to MHC class I. To test the natural antigenicity of the predicted peptides, C57BL/6 mice were immunized with OVA containing immunostimulating complexes to elicit a MHC class I-driven response to naturally processed OVA. The cytolytic potential of the responding T cell population was tested in vitro by using EL-4 cells preincubated with the predicted synthetic peptides as targets. The known antigenic peptide OVA 257-264 elicited a strong response; however, OVA 176-183 was also recognized while the remaining three were not recognized. The CTL response did not strictly correlate with the ability of the selected peptides to bind Kb, for example, OVA 55-62 was able to bind Kb efficiently, yet elicited no cytolytic response. In addition, the plasticity of the peptide-binding motif was probed by making amino acid substitutions, and as a result the motif proved to be more flexible than previously suspected. This represents the first report of a Kb-associated CTL epitope within OVA other than OVA 257-264. It also demonstrates the predictive quality of the Kb-binding motif; however, not all predicted peptides were recognized by primary OVA-induced CTL, implying more rules of processing and binding are needed.

Amino Acid Sequence↗
PubMed1993

The prevalence of primary angle closure glaucoma and open angle glaucoma in Mamre, western Cape, South Africa.

OBJECTIVE: To determine the prevalence of primary angle closure glaucoma in the so-called Cape people of mixed ethnic background. DESIGN: A population-based prevalence study. SETTING: Mamre, a village near Cape Town, South Africa. PARTICIPANTS: Individuals aged 40 years or older. Historically, their ancestors were Southeast Asians and indigenous Africans and, to a lesser extent, Europeans. Of a total of 1194 people, 987 (82.7%) were examined. MAIN OUTCOME MEASURE: Primary angle closure glaucoma was diagnosed in individuals with previous acute or intermittent symptoms of angle closure and in individuals with an "occludable" angle and an intraocular pressure of greater than 21 mm Hg or a glaucomatous visual field. MAIN RESULTS: An age-related trend toward hypermetropia was found, which was greatest in women older than age 50 years. Gonioscopy identified Shaffer grade 1 angles in 89 (9%) of 987 subjects. The prevalence of primary angle closure glaucoma was 2.3% (23 subjects) and increased with age in both sexes. Women were affected more than four times as often as men and the sex difference persisted across all age groups. In comparison, the prevalence of primary open angle glaucoma was 1.5% (15 subjects). Primary glaucoma (angle closure plus open angle) was the leading cause of bilateral blindness in the community, with a prevalence rate of 0.5% (five subjects). CONCLUSIONS: This study identified primary angle closure glaucoma as a significant public health problem in the Western Cape Province. Because of the ethnic back-ground of the people studied, these findings may also apply to the populations of Southeast Asia.

Adult↗
PubMed1993

Platelet activation in patients with thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a rare syndrome of unknown etiology. It is characterized by platelet microthrombi in small vessels, which results in tissue dysfunction and a microangiopathic hemolytic anemia. Activation of coagulation is not a prominent feature of TTP. It is not known whether the process which results in platelet aggregate formation might also activate platelets. Using GMP-140 as a marker of activation, we examined the activation state of circulating platelets in seven TTP patients and three normal controls, as well as the ability of purified platelets from three TTP patients and three controls to be activated in vitro. There was no statistically significant difference in the percentage of activated platelets circulating in patients and controls (4% vs. 2%). Both TTP and control platelets increased GMP-140 expression and procoagulant activity after stimulation with thrombin or the calcium ionophore A23187. Thus, we conclude that TTP patients do not have a significantly increased proportion of circulating activated platelets, and their platelets can be activated normally by thrombin or a calcium ionophore.

Blood Coagulation↗
PubMed1993

Response of blood leukocytes to thrombin receptor peptides.

Thrombin has receptor-mediated effects on a variety of cell types. A recently cloned platelet thrombin receptor exerts its effects by a tethered-ligand mechanism. A similar receptor was shown in at least two nonplatelet cell types, fibroblasts and endothelial cells. Thrombin has biologically important effects on leukocytes, but the type of receptor mediating the effects is not known. Therefore, we examined the responses of monocytes, neutrophils, and lymphocytes to thrombin and to an agonist specific for the platelet-type thrombin receptor. We compared the effects of a peptide (SFLLRNPNDKYEPF) corresponding to residues 42-55 of the cloned platelet thrombin receptor on calcium flux in platelets and leukocytes. The thrombin receptor peptide induced increases in intracellular calcium in platelets and monocytes that reached a maximum at 5 microM peptide. The maximal increase was similar in magnitude to the response to thrombin. Lymphocytes showed a small and variable increase in intracellular calcium in response to thrombin or the thrombin receptor agonist. The thrombin receptor peptide had no effect on neutrophil calcium concentrations. When the amino acid corresponding to Arg 46 was replaced with Ala in the synthetic peptide, the ability to increase intracellular calcium was abolished for both platelets and monocytes. The peptide instead had thrombin antagonist activity. Thus, monocytes respond to thrombin receptor peptides similarly to platelets. We conclude that human monocytes possess a thrombin receptor similar to that present on platelets. Furthermore, the residue corresponding to Arg 46 of the thrombin receptor is critical for receptor agonist activity.

Actins↗
PubMed1993

Linkage analysis of the glucokinase locus in familial type 2 (non-insulin-dependent) diabetic pedigrees.

Glucokinase is among the few genes which may play a key role in both insulin secretion and insulin action. Glucokinase is present in pancreatic beta cells where it may have a key role in the glucose sensing mechanism, and it is present in hepatocytes, where it may participate in glucose flux. Glucokinase defects have recently been implicated in maturity-onset diabetes of the young. To examine the hypothesis that glucokinase plays a key role in the predisposition to common familial Type 2 (non-insulin-dependent) diabetes mellitus, we typed 399 members of 18 Utah pedigrees with multiple Type 2 diabetic individuals for two markers in the 5' and 3' flanking regions of the glucokinase gene. Linkage analysis was performed under both dominant and recessive models. We also repeated these analyses with individuals with impaired glucose tolerance who were considered affected if their stimulated (2-h) glucose exceeded age-specific normal levels for 95% of the population. Under several dominant models, linkage was significantly excluded, and under recessive models log of the odds (LOD) score was less than -1. We were also unable to demonstrate statistical support for the hypothesis that a small subgroup of pedigrees had glucokinase defects, but the most suggestive pedigree (individual pedigree LOD 1.8-1.9) ranked among the youngest and leanest in our cohort. We can exclude a major role for glucokinase in familial Type 2 diabetes, but our data cannot exclude a role for this locus in a minority of pedigrees.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1993

Epidemiology of achalasia in central Israel. Rarity of esophageal cancer.

The epidemiology of achalasia was studied in a predominantly urban, Jewish population of approximately 1.3 million, in central Israel, during the years 1973-1983. One hundred sixty-two proven cases were collected, representing all known patients with achalasia in the study area. There were no gender differences. The majority of cases were diagnosed within two years of onset of symptoms, although the median delay in diagnosis was 4.4 +/- 5.3 years. The disease was rare in the first two decades of life. The prevalence (in 1983) in the first two decades was 0.7/10(5) rising to 36.2/10(5) above age 70. The mean annual incidence in the years 1973-1978 was 0.8/10(5). It rose slightly to a mean annual incidence of 1.1/10(5) in the years 1979-1983. The prevalence of the disease in 1973 and 1983 was 7.9/10(5) and 12.6/10(5), respectively. The age-adjusted prevalence in 1973 was higher in Asian and African born Jews as compared to those born in Europe, America, or Israel. This difference disappeared by the year 1983. No case of cancer of the esophagus was found among our patients. This may be due to the nonselected, regional nature of our series or to the effects of earlier therapy of achalasia in recent decades.

Adult↗
PubMed1993

Poly(epsilon-caprolactone) nanocapsules in carteolol ophthalmic delivery.

In order to increase the ocular absorption of carteolol, this antiglaucomatous drug was incorporated into either nanoparticles (NP) or nanocapsules (NC). The polymer used was poly(epsilon-caprolactone) (PCL). The dosage forms were tested on intraocular hypertensive-induced rabbits. Results are presented as the chronological variations of the intraocular pressure (IOP) in comparison with the commercial aqueous solution (Carteol eye drops). The therapeutic results (decrease in IOP) were much more pronounced with carteolol incorporated into the colloidal carriers than with the commercial eye drops. Further, NC displayed a better effect than NP because the drug was entrapped in the oily core of the carrier, thus more readily available to the eye. The incorporation of the drug into nanocapsules produced a decline in the cardiovascular side effects in comparison with aqueous eye drops, thus showing that the undesired noncorneal absorption was reduced. In conclusion, colloidal suspension made of poly(epsilon-caprolactone) could offer a good opportunity for ophthalmic delivery of drugs.

Animals↗
PubMed1993

Electroencephalogram and computerised cerebral tomography findings in eclampsia.

OBJECTIVE: To define more clearly the neuropathophysiology of eclampsia. DESIGN: A prospective study relating to computerised cerebral tomography (CAT) scan and electroencephalogram (EEG) findings in eclampsia. SETTING: A large referral centre in a developing society. SUBJECTS: Thirty-two women with eclampsia. MAIN OUTCOME MEASURES: Abnormalities in EEG and CAT scan findings. RESULTS: Approximately 45% of the women studied had CAT scan abnormalities, while 90% had EEG abnormalities. A burst suppression pattern on EEG examination was found in four women suggesting a temporary dissolution of cerebral function to the midbrain level as the cause of seizures. CONCLUSIONS: EEGs are probably more sensitive than CAT scans in detecting the extent of the pathology in the brain in women with eclampsia.

Adolescent↗