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M Adler

Publications and source records attributed to M Adler.

At least 73 records · Page 4Linked to original sources
PubMed1998

Homologue scanning mutagenesis of heregulin reveals receptor specific binding epitopes.

The EGF domain of heregulin has all the receptor binding characteristics of full-length heregulin and has strong homology to the ligands for erbB-1. Despite this, it does not bind erbB-1 but instead binds erbB-3 and erbB-4. The sequence similarity between HRG and the erbB-1 ligands suggest that a few residues are responsible for receptor binding specificity. To determine the sequences involved in receptor binding, we performed homologue scanning mutagenesis on the EGF domain of HRGalpha using sequences of TGFalpha or EGF. We found three sets of mutations in the N-terminal subdomain that were responsible for receptor binding specificity. Mutations in the C-terminal subdomain affected the binding affinity, but did appear to confer any specificity.

Adenocarcinoma↗
PubMed1998

The 26-mer peptide released from SNAP-25 cleavage by botulinum neurotoxin E inhibits vesicle docking.

Botulinum neurotoxin E (BoNT E) cleaves SNAP-25 at the C-terminal domain releasing a 26-mer peptide. This peptide product may act as an excitation-secretion uncoupling peptide (ESUP) to inhibit vesicle fusion and thus contribute to the efficacy of BoNT E in disabling neurosecretion. We have addressed this question using a synthetic 26-mer peptide which mimics the amino acid sequence of the naturally released peptide, and is hereafter denoted as ESUP E. This synthetic peptide is a potent inhibitor of Ca2+-evoked exocytosis in permeabilized chromaffin cells and reduces neurotransmitter release from identified cholinergic synapses in in vitro buccal ganglia of Aplysia californica. In chromaffin cells, both ESUP E and BoNT E abrogate the slow component of secretion without affecting the fast, Ca2+-mediated fusion event. Analysis of immunoprecipitates of the synaptic ternary complex involving SNAP-25, VAMP and syntaxin demonstrates that ESUP E interferes with the assembly of the docking complex. Thus, the efficacy of BoNTs as inhibitors of neurosecretion may arise from the synergistic action of cleaving the substrate and releasing peptide products that disable the fusion process by blocking specific steps of the exocytotic cascade.

Amino Acid Sequence↗
PubMed1998

Efficacy of a novel metalloprotease inhibitor on botulinum neurotoxin B activity.

The novel inhibitor 7-N-phenylcarbamoylamino-4-chloro-3-propyloxyisocoumarin (ICD 1578) was tested for its ability to antagonize the zinc metalloprotease activity of botulinum toxin B (BoNT/B). The efficacy of this compound was tested in a cell-free system using a 50-mer synaptobrevin peptide as substrate. The peptide, designated as [Pya88] S 39-88, had a fluorescent amino acid analog, L-pyrenylalanine (Pya), substituted for the normal Phe88 of synaptobrevin-2. Cleavage by BoNT light chain yielded fragments of 38 and 11 amino acids, respectively. The smaller fragment, containing the Pya fluorophore, was readily separated and quantified by fluorescence spectroscopy at 377 nm. In the presence of 7-200 microM ICD 1578, cleavage of [Pya88] S 39-88 was progressively reduced (IC50 = 27.6 microM), and 100 microM ICD 1578 produced >95% inhibition. For comparison, captopril, a well-known zinc metalloprotease inhibitor, generated less than 10% inhibition at a concentration of 5 mM. ICD 1578 is the most potent antagonist of BoNT/B light chain thus far described.

Botulinum Toxins↗
PubMed1998

Pupillographic assessment of sleepiness in sleep-deprived healthy subjects.

Spontaneous pupillary-behavior in darkness provides information about a subject's level of sleepiness. In the present work, pupil measurements in complete darkness and quiet have been recorded continuously over 11-minute period with infrared video pupillography at 25 Hz. The data have been analyzed to yield three parameters describing pupil behavior; the power of diameter variation at frequencies below 0.8 Hz (slow changes in pupil size), the pupillary unrest index, and the average pupil size. To investigate the changes of these parameters in sleep deprivation, spontaneous pupillary behavior in darkness was recorded every 2 hours in 13 healthy subjects from 19:00 to 07:00 during forced wakefulness. On each occasion, comparative subjective sleepiness was assessed with a self-rating scale (Stanford Sleepiness Scale, SSS). The power of slow pupillary oscillations (< or = 0.8 Hz) increased significantly and so did the values of SSS, while basic pupil diameter decreased significantly. Slow pupillary oscillations and SSS did not correlate well in general but high values of pupil parameters were always associated with high values in subjective rating. Our results demonstrate a strong relationship between ongoing sleep deprivation and typical changes in the frequency profiles of spontaneous pupillary oscillations and the tendency to instability in pupil size in normals. These findings suggest that the results of pupil data analysis permit an objective measurement of sleepiness.

Adult↗
PubMed1998

Expression of transforming growth factor beta receptors in normal human colon and sporadic adenocarcinomas.

BACKGROUND & AIMS: An absence or a presence of mutated transforming growth factor (TGF)-beta receptors is a possible hypothesis explaining the resistance of cancer cells to the growth-inhibitory effect of TGF-beta. Mutations involving microsatellite-like regions of the type II TGF-beta receptor have been described in subgroups of colorectal cancers. The aim of this study was to investigate the expression and distribution of TGF-beta receptors in sporadic colorectal cancers and normal tissues. METHODS: Thirty-three sporadic colorectal cancers and 20 normal colonic tissues were explored by immunohistochemistry for the expression of type I and type II TGF-beta receptors. Eighteen tumor and 20 normal samples were used for radioactive thermocycling and sequencing of the two microsatellite-like regions of the type II receptor. RESULTS: Both receptors were overexpressed in tumors compared with normal samples. There was a relationship between the abundance of type II receptor expression and the degree of differentiation of the tumors but not the Dukes' staging or the localization of the neoplasias. No mutation was observed in the microsatellite-like regions of receptor II in any of the samples. CONCLUSIONS: Sporadic colorectal cancers do not show an absence or a presence of mutated TGF-beta receptors that could explain a resistance to TGF-beta-mediated growth inhibition. The pathways to tumorigenesis of sporadic colorectal cancers may be different from those of some hereditary ones.

Adenocarcinoma↗
PubMed1998

Colour vision in normal subjects tested by the colour arrangement test 'Roth 28-hue desaturated'.

The aim of the study was to obtain normal values for the colour-arrangement test, Roth 28-hue desaturated. In 146 healthy non-smokers colour vision was tested monocularly. The subjects were divided into four age groups: 0-19, 20-39, 40-59, and 60-79 years. The overall error score for all groups was 54 +/- 24 (median +/- mean absolute deviation). The values for the 20-39 year group were significantly lower than those for the other groups (Kruskal-Wallis: P < 0.0001 with subsequent multiple Mann-Whitney test). An increasing predominance of errors along the blue-yellow-axis was observed with increasing age. The error scores of normal subjects tested by the Roth 28-hue desaturated were comparable with those on the well-known Farnsworth-Munsell 100-hue (FM-100). Because the Roth 28-hue desaturated is shorter and simpler to administer, it is an alternative to the FM-100 in situations that need to assess colour discrimination and error axis quantitatively and quickly.

Adolescent↗
PubMed1998

Mathematical procedures in data recording and processing of pupillary fatigue waves.

Spontaneous pupillary behaviour in darkness provides information about a subject's level of vigilance. To establish infrared video pupillography (IVP) as a reliable and objective test in the detection and quantification of daytime sleepiness, the definition of numerical parameters is an important precondition characterising spontaneous pupil behaviour adequately for further statistical procedures. The correct measurement of the pupil size, even if the lid or eyelashes are occluding the pupil, is of particular concern when testing vigilance. In this case many edge points of the pupil are detected and a fitting procedure is described that fits these edge points to a circle and excludes outliers. The first step of data preparation consists of a mathematical artefact management consisting of blink detection and elimination, followed by interpolation. Second, a fast Fourier transformation is carried out for frequencies from 0.0 to 0.8 Hz for each time segment of 82 s. Results are given in absolute and relative power of each frequency band per time segment and mean values over the entire record of 11 min. Third, the changes of the mean pupillary diameter per data window against time are shown graphically. An additional parameter referring to the pupil's tendency to instability, the pupillary unrest index (PUI), is defined by cumulative changes in pupil size based on mean values of consecutive data sequences. These mathematical procedures provide a high level of quality in both data collection and evaluation of IVP as an objective test of vigilance. In a pilot study, the pupillary behaviour of two groups were measured. One group rated themselves as alert (ten men), the other group as sleepy (12 men). The power and PUI were compared using the Mann-Whitney U-test. Both parameters show significant differences between the two groups.

Data Interpretation, Statistical↗
PubMed1998

Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: a multicenter randomized trial. Groupe CHC.

BACKGROUND/AIMS: Lipiodol chemoembolization is a widely used method of treatment in patients with unresectable hepatocellular carcinoma, but its efficacy is still debated. The aim of our study was to assess the efficacy of lipiodol chemoembolization in patients with unresectable hepatocellular carcinoma. METHODS: Seventy-three patients with unresectable hepatocellular carcinoma, but without severe liver disease or portal vein occlusion, were randomly assigned to receive either repeated lipiodol chemoembolization (lipiodol, cisplatin (2 mg/kg), lecithin, and gelatin sponge injected into the hepatic artery) plus tamoxifen (40 mg) or tamoxifen alone. The main end-point was survival. RESULTS: The 37 patients in the lipiodol chemoembolization group received 104 courses (median 3 per patient). By 1 September 1996, 58 patients had died: 30 in the lipiodol chemoembolization group and 28 in the tamoxifen group. There was no difference in survival between the two groups (p=0.77). The relative risk of death in the lipiodol chemoembolization plus tamoxifen group as compared to the tamoxifen group was 0.92 (95% confidence interval 0.55 to 1.56). At 1 year, survival was 51% and 55%, respectively. An objective tumoral response was more frequently observed in the lipiodol chemoembolization group than in the tamoxifen group (24 versus 5.5%, respectively, p=0.046). Lipiodol chemoembolization caused two deaths and induced signs of liver failure in 51% of the patients assigned to this treatment. CONCLUSION: In our randomized study, lipiodol chemoembolization did not improve the survival of patients with unresectable hepatocellular carcinoma treated with tamoxifen.

Adult↗
PubMed1998

Efficacy of interferon dose and prediction of response in chronic hepatitis C: Benelux study in 336 patients.

BACKGROUND/AIMS: In an attempt to improve the limited efficacy of treatment of chronic hepatitis C with interferon-alpha 3 MU tiw, we studied the effects of double-dose therapy followed by downward titration, and analyzed the pre- and pertreatment factors associated with response or non-response. METHODS: Three hundred and fifty-four consecutive patients in 19 centers were randomized to interferon-alpha 3 MU tiw for 6 months or 6 MU tiw for 8 weeks followed by down-titration (3,1 MU tiw) till alanine aminotransferase remained normal and plasma HCV RNA was repeatedly undetectable. The primary outcome measure was sustained alanine aminotransferase and HCV RNA response 6 months after treatment. RESULTS: Three hundred and thirty-six patients received treatment. The sustained response rate for patients receiving 3 MU tiw for 6 months was 14% (9-21%,) and for patients receiving double dose tiw for 8 weeks and thereafter titrated therapy 15% (10-21%) (p=0.8). Pretreatment factors associated with a sustained alanine aminotransferase plus HCV RNA response were the absence of cirrhosis, presence of genotype 2 or 3, a low viral load and, in addition, a low alanine aminotransferase/aspartate aminotransferase ratio; a model was developed to allow estimation of the chance of response for the individual patient. The most powerful predictor of sustained response, however, was plasma HCV RNA at week 4; a positive test virtually precluded a sustained response (1.7%, 0.4-5.0%). If week 4 HCV RNA was not detectable, the chance of a sustained response was 21% (12-34%) for genotype 1 versus 40% (28-54%) for the others (p=0.02). Six MU tiw led to a significantly higher week 4 HCV RNA response (47% not detectable) than 3 MU (37%) (p=0.02). During down-titration this difference in viral on-treatment response was lost. CONCLUSIONS: In the treatment of hepatitis C, an early HCV RNA response is a prerequisite for long-term efficacy. Doubling the initial interferon dose increases this early response, but subsequent downward titration negates this effect, especially in genotype 1.

Adult↗
PubMed1998

Production of an expression system for a synaptobrevin fragment to monitor cleavage by botulinum neurotoxin B.

Recombinant DNA techniques were used to develop an expression system for a 51-amino acid peptide fragment that encompasses residues 44-94 of human synaptobrevin 2. This protein is associated with secretory vesicles of nerve terminals and is a substrate for four of the seven serotypes of botulinum neurotoxin (BoNT). The DNA for the recombinant peptide was amplified by the polymerase chain reaction and cloned into the pTrxFus vector. The resulting synaptobrevin peptide was expressed as a thioredoxin fusion protein in E. coli and released into the medium by osmotic lysis. The 18.7-kDa thioredoxin-synaptobrevin protein, designated as TSB-51, is intended for use in a cell-free assay to test potential inhibitors of BoNT/B-mediated proteolysis of synaptobrevin with the ultimate aim of developing clinically effective therapeutic agents to counteract botulism. Incubation of TSB-51 with the purified light chain of BoNT/B resulted in proteolysis which was evident within 30 min and increased with time until completion (approximately 4 hr). Cleavage of TSB-51 appeared to be at the appropriate BoNT/B cleavage site as indicated by a reduced intensity of the 18.7-kDa band and the appearance of a band at 16.4 kDa on Tris-tricene polyacrylamide gradient gels. The concentration of free Zn2+ had a significant effect on the cleavage rate; low Zn2+ concentrations stimulated substrate cleavage, whereas high concentrations were inhibitory. Cleavage was not significantly depressed by the naturally occurring metalloprotease inhibitor phosphoramidon when tested at concentrations up to 5 mM. TSB-51 appears to be a useful substrate for studying BoNT/B and is expected to aid in the discovery of effective BoNT inhibitors.

Amino Acid Sequence↗
PubMed1998

A simple method for carbohydrate-deficient transferrin measurements in patients with alcohol abuse and hepato-gastrointestinal diseases.

Carbohydrate-deficient transferrin (CDT) is known to be increased in alcohol abuse. Several methods were developed for its measurement (e.g. isoelectric focusing with Western blotting or immunofixation, anion-exchange chromatography followed by immunoassays). We describe a greatly simplified isoelectric focusing technique which does not require immunofixation. CDT results obtained with this method were compared to other biological markers of alcohol abuse, i.e. mean corpuscular volume (MCV), aspartate aminotransferase (ASAT) and gamma-glutamyl-transferase (GGT), in 55 patients distributed in three groups (i.e. healthy control subjects, control patients suffering from various hepato-gastrointestinal diseases and alcohol abusing patients). Sensitivity and specificity were 33-89%, 61-57%, 89-49% and 83-100% for MCV, ASAT, GGT and CDT, respectively. We conclude that our method is highly suitable for routine clinical use.

Alcoholism↗
PubMed1998

Mortality among Pennhurst class members, 1978 to 1989: a brief report.

Pennhurst Center closed in 1987, and the closure was one of the most intensely studied of all deinstitutionalizations. Because of recent interest in mortality after deinstitutionalization, we examined all deaths from 1978 to 1989 among the people who had resided at Pennhurst in 1978. During the period from 1978 to 1989, every person moved from Pennhurst to a community home. Relocation literature would suggest that this might be a time of high risk of mortality. However, the actual mortality rates were considerably lower than what would have been expected if Pennhurst had remained in operation, even though the stress of relocation was present. Movement to community homes appeared to improve survival for the Pennhurst people.

Cohort Studies↗
PubMed1998

Hepatitis C virus genotypes: epidemiological and clinical associations. Benelux Study Group on Treatment of Chronic Hepatitis C.

In a cohort of 292 chronic hepatitis C patients living in the Benelux countries the relationship between viral genotype and geographical origin, route of transmission, clinical characteristics and severity of liver disease was analyzed. HCV-RNA isolates could be classified by the Line Probe Assay (LiPA) as 1a, 1b, 2, 3, 4 or 5 in 286 (98%) cases. Patients of European origin were predominantly infected with HCV subtype 1b (164/254, 65%, CI 58-70%), as were patients of Asian origin (7/13, 54%). Patients originating from Surinam (South America) had predominantly type 2 (9/10, 90%), whereas Africans were mainly infected with type 4 (7/9, 77%). Blood transfusion was the mode of transmission in 142 (50%) patients, intravenous drug abuse (IVDA) in 40 (14%), occupational needle accident or tattoo in 11 (4%); no obvious source of infection was found in 93 (33%). In patients infected by blood transfusion, subtype 1b was predominant (70%, CI 61-77%), whereas subtypes la and 3 were predominant in those infected by IVDA (25% and 45%, respectively, p<0.001). Cirrhosis was observed in 68 (24%) patients; in multivariate analysis, factors independently related to cirrhosis were: the duration of infection, age and prior hepatitis B. No significant relationship was found between the severity of fibrosis or liver inflammation and the HCV (sub)types. In summary, in this large cohort of patients in the Benelux countries the hepatitis C virus (sub)type present was clearly related to the country of origin and the route of transmission, but not to the severity of liver disease.

Adult↗
PubMed1998

[Cap polyposis: a rare syndrome].

We report a case of inflammatory cap polyposis of the colon, a rare syndrome, affecting the rectosigmoid. It was observed in a context of mucous diarrhea. Endoscopic and radiological features consisted of elevated and umbilicated nodular lesions. Histology revealed polypoid lesions containing elongated crypts with superficial abrasions, covered by inflammatory and fibrinoid material. Etiopathogenesis of this new syndrome is unknown.

Colon, Sigmoid↗
PubMed1997

Trends and differential use of assistive technology devices: United States, 1994.

OBJECTIVE: This report presents data on annual estimates of the prevalence of use of selected assistive technology devices for vision, hearing, mobility, and orthopedic impairments, including missing limbs. Also presented are statistics on trends in the prevalence of use of selected mobility assistive technology devices for the years 1980, 1990, and 1994. METHODS: The data used for this report are from the 1994 National Health Interview Survey on Disability (NHIS-D), Phase I, which was co-sponsored by a consortium of U.S. Federal agencies and private foundations. All estimates are based on data from the NHIS-D, Phase I, which represent the civilian, noninstitutional population of the United States. RESULTS: An estimated 7.4 million persons in the U.S. household population used assistive technology devices for mobility impairments, 4.6 million for orthopedic impairments (including missing limbs), 4.5 million for hearing impairments (not including impairments fully compensated by hearing aids), and 0.5 million for vision impairments. Use of any mobility device for all ages had the highest prevalence rate at 28.5 per 1,000 persons. There was a positive correlation between an increase in age and the increase in the prevalence rate of device usage; for example, of persons in the age group 65 years and over, the rate of mobility, hearing, and vision device usage was more than 4 times the rate for the total population. CONCLUSION: Assistive technology use has increased because of population size, age composition changes, and a change in the rate of use. Medical and technological advances along with public policy initiatives have also contributed to increased usage.

Adolescent↗