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Biomedical subjects

M Adler

Publications and source records attributed to M Adler.

At least 37 records · Page 2Linked to original sources
PubMed2001

[Therapeutic approach to chronic hepatitis B and C in the dawn of the third millenium].

We try to illustrate the latest developments in epidemiology, pathogenesis and natural history of hepatitis B and C virus infection. Practical management of the patient with chronic B and C liver disease is presented. Universal hepatitis B vaccination should be encouraged in order to reduce to zero morbidity and mortality attributable to liver disease and its complications. Patients at risk for hepatitis B or C infection should be screened and notified about their evolutive risk and the therapeutic possibilities.

Carcinoma, Hepatocellular↗
PubMed2001

[Individual screening for colorectal cancer: which strategy for which patient?].

Currently, more than 4,000 newly colorectal cancer are diagnosed each year in Belgium. The individual average-risk for developing colorectal cancer is about 5%. 90% of colorectal cancer occurred after the age of 50, and in 70% of the cases in patients without particular risk factors (average-risk population). Personal and/or familial history of colorectal adenoma, colorectal cancer, inflammatory bowel disease localised to the colon, familial polyposis syndrome or Hereditary Non Polyposis Colorectal Cancer (HNPCC) increase the risk of colorectal cancer. An individual appropriate screening of high-risk patients and average-risk asymptomatic patients older than 50, together with endoscopic resection of adenoma decrease the incidence and the mortality of colorectal cancer. Usual screening methods are fecal occult blood testing which is not proven to be efficient alone for individual screening (but still recommended for general population's screening), sigmoidoscopy (which has to be completed by a colonoscopy, if lesions founded), and colonoscopy. Virtual colonoscopy and genetic testing need further evaluation. Currently, colonoscopy seems to be the goldstandard method providing complete examination of the whole colon and being the most cost-effective method. Screening strategy should be decided on an individual basis considering the patient's benefit with respect to the informed consent.

Algorithms↗
PubMed2001

[Screening for colorectal cancer by endoscopy: rectosigmoidoscopy or coloscopy?].

Screening for colorectal cancer is almost uniformly recommended for average-risk asymptomatic persons aged 50 years and older and it may substantially reduce its relative mortality. However, consensus is lacking about the type of screening test. Flexible sigmoidoscopy followed by colonoscopy in the presence of adenoma(s), detect 70% of the neoplasms and should be recommended for adults aged 50 years and older. Colonoscopy with polypectomy may ultimately become the preferred strategy after 60 years and certainly in the presence of alarm signs and personal or familial risks for colorectal cancer.

Age Distribution↗
PubMed2000

Preparation, characterization, and the crystal structure of the inhibitor ZK-807834 (CI-1031) complexed with factor Xa.

Factor Xa plays a critical role in the formation of blood clots. This serine protease catalyzes the conversion of prothrombin to thrombin, the first joint step that links the intrinsic and extrinsic coagulation pathways. There is considerable interest in the development of factor Xa inhibitors for the intervention in thrombic diseases. This paper presents the structure of the inhibitor ZK-807834, also known as CI-1031, bound to factor Xa and provides the details of the protein purification and crystallization. Results from mass spectrometry indicate that the factor Xa underwent autolysis during crystallization and the first EGF-like domain was cleaved from the protein. The crystal structure of the complex shows that the amidine of ZK-807834 forms a salt bridge with Asp189 in the S1 pocket and the basic imidazoline fits snugly into the S4 site. The central pyridine ring provides a fairly rigid linker between these groups. This rigidity helps minimize entropic losses during binding. In addition, the structure reveals new interactions that were not found in the previous factor Xa/inhibitor complexes. ZK-807834 forms a strong hydrogen bond between an ionized 2-hydroxy group and Ser195 of factor Xa. There is also an aromatic ring-stacking interaction between the inhibitor and Trp215 in the S4 pocket. These interactions contribute to both the potency of this compound (K(I) = 0.11 nM) and the >2500-fold selectivity against homologous serine proteases such as trypsin.

1-Carboxyglutamic Acid↗
PubMed2000

Sex differences in thermoregulation after acute and chronic morphine administration in mice.

Sex differences in thermoregulation have been reported following acute morphine administration in rats only. This study assessed whether male and female mice also differ in thermoregulatory responses following acute and chronic morphine administration. Females displayed significantly higher baseline colorectal temperature and greater morphine (24mg/kg, s.c.) hypothermia (2. 5-fold) on day 1. Two additional days of morphine treatment did not alter baseline temperature readings on Day 4 in either sex, but significantly reduced the morphine hypothermia relative to Day 1 in a sex-dependent manner. Whereas the morphine hypothermia was completely abolished in males, significant hypothermia was still observed in females. Acute and chronic saline injections had no effect on colorectal temperature. The data demonstrate sex differences in the thermoregulatory responses to acute and chronic morphine administration in mice.

Animals↗
PubMed2000

Modified genetic algorithm resolves ambiguous NOE restraints and reduces unsightly NOE violations.

In an ideal world, every NOE cross peak would have a unique assignment. However, the interpretation of NOE peaks is frequently complicated by overlapping resonances. In theory, ambiguous assignments could be resolved by performing separate structure calculations with each possible interpretation. Unfortunately, this would require an astronomical amount of computing time. A modified genetic algorithm has been developed that efficiently resolves hundreds of ambiguous restraints in parallel. Each NOE assignment becomes a gene that can be passed on to a new generation. New individuals are constructed by making a constraint lists from a subset of the genes. The constraint lists are then tested for self-consistency by using molecular dynamics to generate new structures for each list. To a first-degree approximation, there is enough information retained in each list to determine the global fold of the protein. Self-consistent constraint lists receive higher scores and their genes (or NOEs) stand a better chance of surviving into the next generation. The process selects NOEs that are consistent with the global fold. Under normal conditions, the program converges in 3 to 8 generations using 70 structures per generation. The final constraints are self-consistent and contain almost no residual NOE violations.

Algorithms↗
PubMed2000

Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry.

Potent and selective inhibitors of inducible nitric oxide synthase (iNOS) (EC ) were identified in an encoded combinatorial chemical library that blocked human iNOS dimerization, and thereby NO production. In a cell-based iNOS assay (A-172 astrocytoma cells) the inhibitors had low-nanomolar IC(50) values and thus were >1,000-fold more potent than the substrate-based direct iNOS inhibitors 1400W and N-methyl-l-arginine. Biochemical studies confirmed that inhibitors caused accumulation of iNOS monomers in mouse macrophage RAW 264.7 cells. High affinity (K(d) approximately 3 nM) of inhibitors for isolated iNOS monomers was confirmed by using a radioligand binding assay. Inhibitors were >1,000-fold selective for iNOS versus endothelial NOS dimerization in a cell-based assay. The crystal structure of inhibitor bound to the monomeric iNOS oxygenase domain revealed inhibitor-heme coordination and substantial perturbation of the substrate binding site and the dimerization interface, indicating that this small molecule acts by allosterically disrupting protein-protein interactions at the dimer interface. These results provide a mechanism-based approach to highly selective iNOS inhibition. Inhibitors were active in vivo, with ED(50) values of <2 mg/kg in a rat model of endotoxin-induced systemic iNOS induction. Thus, this class of dimerization inhibitors has broad therapeutic potential in iNOS-mediated pathologies.

Allosteric Regulation↗
PubMed2000

Antagonism of botulinum toxin A-mediated muscle paralysis by 3, 4-diaminopyridine delivered via osmotic minipumps.

The ability of 3,4-diaminopyridine (3,4-DAP) to antagonize muscle paralysis following local injection of botulinum neurotoxin A (BoNT/A) complex was evaluated in the in situ rat extensor digitorum longus (EDL) preparation. The minipumps were implanted 6 h prior to BoNT/A administration and delivered their contents over a 7-day period producing a steady plasma 3,4-DAP concentration of 27-29 microM. In the absence of 3,4-DAP, a local injection of five mouse LD(50) units of BoNT/A led to total paralysis of EDL muscles within 24 h of application. Recovery from paralysis was slow, remaining at <30% of control 14 days after toxin injection. 3,4-DAP delivery by osmotic minipumps antagonized the actions of BoNT/A on neuromuscular transmission. Seven days after the onset of 3,4-DAP infusion, indirectly elicited twitch and tetanic tensions in BoNT/A-injected EDL muscles were 72.4 and 46.9% of control, respectively. In the absence of 3,4-DAP, twitch and tetanic tensions were only 5.4 and 15. 1% of control. The benefits conferred by 3,4-DAP treatment were not maintained after minipumps were removed. Seven days after cessation of 3,4-DAP infusion, twitch and tetanic tensions were not significantly different from those observed in muscles receiving BoNT/A alone. It is concluded that 3,4-DAP may be useful for treatment of BoNT/A-induced muscle paralysis, but sustained delivery of the drug would be required for the entire period of BoNT intoxication to maintain muscle function.

4-Aminopyridine↗
PubMed2000

Surface composition of spray-dried particles of bovine serum albumin/trehalose/surfactant.

PURPOSE: To characterize via electron spectroscopy for chemical analysis (ESCA) the surface of spray-dried particles of trehalose plus a protein (bovine serum albumin). Additionally, to show how and why the addition of a surfactant reduces protein adsorption, and by this mechanism could reduce protein instability during spray-drying. METHODS: Aqueous solutions of trehalose plus bovine serum albumin (bSA) were spray-dried with increasing concentrations of surfactant. The surface composition of the dried particles was examined using ESCA. RESULTS: The presence of bSA, trehalose, and surfactant could be detected quantitatively in the particle surface. In the absence of surfactant the bSA had a large surface excess concentration (determined via its N atoms). Increasing concentration of polysorbate 80 reduced the surface excess of bSA in a concentration-dependent manner. At high polysorbate 80 concentration (5 mg/ml) the bSA could no longer be detected in solid surface. Using sodium dodecyl sulfate it was shown that the reduction in surface concentration of the protein is accompanied by a simultaneous increase in surface concentration of the surfactant. Neither surfactant fully covers the surface at the point of complete protein exclusion. CONCLUSIONS: ESCA provides a direct, quantitative measure of the surface composition of spray-dried trehalose/protein/surfactant particles. Surfactant reduces protein adsorption at the water/air-interface. This appears to be a result of complex formation with the surfactant within the bulk spray solution.

Animals↗
PubMed2000

Bone metastases from thyroid carcinoma: clinical characteristics and prognostic variables in one hundred forty-six patients.

To describe the clinical characteristics and define the indicators that best predict survival in patients with bone metastases from thyroid carcinomas. We collected data from medical records of 146 patients with documented bone metastases from thyroid carcinoma seen at our medical center over a 38-year period. Univariate and multivariate analyses of prognostic indicators for survival were performed. Bone metastases were present at the initial diagnosis in 47% of patients. Vertebrae (29%), pelvis (22%), ribs (17%), and femur (11%) were the most common sites of metastases. Multiple lesions were present in 53% of the cases. The overall 10-year survival rate from the time of diagnosis of thyroid cancer was 35%, and from diagnosis of initial bone metastasis was 13%. By univariate analysis from the time of the initial bone metastasis, radioiodine uptake by skeletal metastases, the absence of nonosseous metastases and treatment with radioiodine were significant prognostic factors. By multivariate analysis, radioiodine uptake by skeletal metastases and the absence of nonosseous metastases were independent favorable prognostic variables for survival. In a subgroup of patients in which histologic specimens were available and were reviewed, Hurthle cell carcinoma was the most favorable histologic subtype for survival with the undifferentiated subtype being the worst. The spread of thyroid carcinoma to bone is more common in patients over 45 years of age, is usually symptomatic, and is often multicentric. Overall survival is best in those whose lesions concentrate radioactive iodine and those who have no nonosseous metastases.

Adult↗
PubMed2000

Cefdinir vs. amoxicillin/clavulanic acid in the treatment of suppurative acute otitis media in children.

An investigator-blinded, randomized, multicenter study was conducted to compare the efficacy and safety of cefdinir and amoxicillin/ clavulanate (amoxicillin/CA) in the treatment of pediatric patients with acute suppurative otitis media. Patients 6 months to 12 years of age were randomized in a 1:1:1 ratio to receive cefdinir 14 mg/kg once-daily, cefdinir 7 mg/kg b.i.d., or amoxicillin/CA 13.3 mg/kg t.i.d. Test-of-cure was determined 11 to 16 days posttherapy. Of the 752 patients who entered the study, 665 (88%) completed treatment and 595 (79%) were evaluable. Response rates in the three treatment groups were similar. Overall rates of adverse events were statistically lower in the cefdinir once-daily group than in the amoxicillin/CA group. Diarrhea was the most common adverse event in all treatment groups. Cefdinir given either once-daily or twice-daily is a safe and effective treatment for pediatric patients with acute suppurative otitis media.

Acute Disease↗
PubMed2000

Childhood experiences and adult behavior in a group of women with pain accounted for by psychological factors and a group recovered from major depression.

OBJECTIVE: In this study twenty-four women with pain accounted for by psychological factors (DSM-IV, 307.80) and twenty-four with major depression diagnosed according to DSM-III-R were compared to study the relationship between pain and depression. METHOD: They were examined by a semi-structured, tape-recorded interview to study their childhood experiences and adult behavior. The interviews were rated by two independent and blind raters. Interrater correlation (Cohen-Kappa) varied between good and close agreement. RESULTS: Of childhood experiences, "brutality between parents," "brutality toward child," and "sexual abuse" were often found in both groups and were more strongly represented in these than in comparison groups of former studies. As adults, the pain group had experienced more serious illness (p = 0.037) and surgery (p = 0.014). The depression group more often had a history of depression (15/24 vs. 4/24; p = 0.001). The pain group spoke negatively of its physicians (p = 0.001), was more hostile during the interview (p = 0.041), was less convinced of the benefit of the hospital stay (p = 0.029), felt less self-responsible, and was more pessimistic (p = 0.013). The pain patients also provoked negative emotions in the raters, whereas the latter's reaction to the depression group was compassion and interest (p = 0.0005) (Pearson's chi2 and Fisher's exact tests). CONCLUSIONS: The results show that negative childhood experiences are prominent and similar in patients with pain accounted for by psychological factors and in patients after major depression. Adult behavior, however, is very different.

Adult↗
PubMed2000

Bone metastases from thyroid carcinoma: a histopathologic study with clinical correlates.

CONTEXT: Only limited information exists on the pathologic aspects of thyroid carcinomas with bone metastases, most large studies having concentrated mainly on their clinical features. OBJECTIVE: To study in detail the morphologic features of thyroid carcinomas with skeletal metastases. DESIGN: Seventy-nine cases of thyroid carcinoma with bone metastases treated at Memorial Sloan-Kettering Cancer Center, New York, NY, between 1964 and 1998 were investigated, with emphasis on the pathology of the primary and/or metastatic tumors and comparison of the morphologic features of the tumors at both the sites, wherever possible. The tumors were also compared for various clinical parameters. RESULTS: The cohort consisted of 22 papillary, 17 follicular, 16 insular, 10 anaplastic, 9 Hürthle cell, and 5 medullary carcinomas. Of these cases, 68% had poorly differentiated or undifferentiated features in the primary and/or metastatic tumors. The metastatic tumors were better differentiated than the primary in one third of the cases (6 of 18). Only one case showed a less differentiated metastasis. The overall 5- and 10-year survival probabilities after the bone metastases were 29% and 13%, respectively (Kaplan-Meier method). Although both the tumor type and differentiation seemed to affect survivals after bone metastasis (P =.007 and.012, respectively) (log-rank test), this was primarily due to the much worse prognosis in the cases of anaplastic and medullary carcinoma. Cases of Hürthle cell carcinoma showed the longest median survival. There was no significant difference in survival among patients up to or older than 45 years at the time of metastases (P =.31). CONCLUSIONS: Most thyroid carcinomas with bone metastases are of papillary type, and most have poorly differentiated or undifferentiated features. The influence of the microscopic tumor type and tumor differentiation on survival after bone metastasis primarily appears to be due to the much worse prognosis among anaplastic and medullary carcinomas. Age at diagnosis of bone metastases does not influence survivals.

Adenocarcinoma↗