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Biomedical subjects

R Herrmann

Publications and source records attributed to R Herrmann.

At least 91 records · Page 5Linked to original sources
PubMed1999

Merosin-positive congenital muscular dystrophy with transient brain dysmyelination, pontocerebellar hypoplasia and mental retardation.

The congenital muscular dystrophies (CMDs) are a heterogeneous group of disorders. Among these, the laminin alpha 2 chain 'merosin' deficient CMD is caused by mutations of the LAMA2 gene on chr 6q2 and Fukuyama CMD is linked to chr 9q31. We report a 7-year-old boy who was born to consanguineous healthy parents. His motor and mental development were slow. Creatine kinase (CK) was elevated (2.100 U/l), and the muscle biopsy was dystrophic. He sat unsupported at 12 months and took his first steps at 3 years of age. At 6 years of age he could walk up to 500 m. He was mentally retarded and spoke single words only. At 1 year, MR imaging of the brain showed abnormal increased periventricular T2-signal, consistent with dysmyelination as well as pontocerebellar hypoplasia and several cerebellar cysts. The pattern of gyration was normal. Follow-up at 4 years showed normalization of the previously abnormal periventricular T2-signal. Immunohistochemical analysis of the skeletal muscle showed normal expression of laminin alpha 2 for a C-terminal antibody and antibodies to the 300 and 150 kDa fragments, as well as of laminins alpha 5, beta 1, beta 2 and gamma 1. The boy has two healthy younger brothers. Linkage analysis excluded the candidate loci on chromosomes 6q2 and 9q31. As such, the patient's data are suggestive of a new form of laminin alpha 2 positive CMD characterized by transient brain dysmyelination, pontocerebellar hypoplasia and mental retardation.

Biopsy↗
PubMed1999

Quality of life as subjective experience: reframing of perception in patients with colon cancer undergoing radical resection with or without adjuvant chemotherapy. Swiss Group for Clinical Cancer Research (SAKK)

PURPOSE AND BACKGROUND: We examined whether patients with colon cancer undergoing surgery with or without adjuvant chemotherapy change the internal standards on which they base their quality-of-life (QL) estimation, and, if they do so, whether this reframing alters interpretation of QL findings. These questions were addressed within a randomized clinical trial of the Swiss Group for Clinical Cancer Research (SAKK 40/93). PATIENTS AND METHODS: After radical resection of adenocarcinoma of the colon (pT1-4pN > 0M0 and pT3-4pN0M0) and perioperative chemotherapy, patients were randomized to three treatment arms: observation only (A), 5-FU 450 mg/m2 plus Levamisol (B), or 5-FU 600 mg/m2 (C). QL was measured by linear analogue self-assessment indicators. Patients estimated their pre-surgery QL both before surgery and retrospectively thereafter, and their pre-adjuvant QL both at the beginning of randomly assigned chemotherapy or observation and retrospectively about two months later. Thereafter, current QL was assessed. Paired t-tests were used to test the hypotheses of no change. RESULTS: Overall, 187 patients with at least one pair of corresponding questionnaires were analyzed. Patients estimated their pre-surgery QL after surgery significantly lower than before and their pre-adjuvant QL under treatment or observation also lower than at the beginning. In the adjuvant phase, in contradiction to our hypothesis, chemotherapy had almost no impact on these changes attributed to reframing. Conventionally assessed changes indicated an improvement in QL. Patients with treatment C reported less improvement in functional performance than those with B or those under observation (P = 0.04). Patients with treatment B indicated a greater worsening in nausea/vomiting than those with C, whereas patients with observation only showed an improvement (P = 0.0009). After adjustment of current QL scores under treatment or observation to patients' retrospective estimation, the treatment effects were diluted but the overall improvement was substantially amplified in most QL indicators. CONCLUSIONS: Patients with colon cancer substantially reframe their perception in estimating QL both under radical resection and under adjuvant chemotherapy or observation. This effect is an integral part of patients' adaptation to disease and treatment. An understanding of this phenomenon is of particular relevance for patient care. Its role in evaluating QL endpoints in clinical trials needs further investigation.

Adenocarcinoma↗
PubMed1999

Axl expression is associated with adverse prognosis and with expression of Bcl-2 and CD34 in de novo acute myeloid leukemia (AML): results from a multicenter trial of the Swiss Group for Clinical Cancer Research (SAKK).

Receptor tyrosine kinases (RTK) play a significant role in the signal transduction of normal, and malignant hematopoietic cells. We have previously shown that Axl, a novel RTK, is mainly expressed in leukemias of myeloid origin, and that its expression may be associated with cells of monocytic origin. Since expression of certain RTKs in cancer may be associated with different biology and survival, we investigated whether the expression of Axl is associated with clinical characteristics and survival in acute myeloid leukemia (AML). RNA from 54 patients with AML treated in a cooperative group trial was analyzed in a retrospective and blinded manner using a semi-quantitative reverse transcriptase polymerase chain reaction-based assay with primers specific for the Axl gene. Axl expression was found in 19 out of the 54 cases (35%). Axl expression was not detected more frequently in patients of older age, specific FAB categories, or cases with extramedullary disease. However, there existed a correlation between Axl and bcl-2 expression levels. AML cells with high bcl-2 expression showed higher Axl expression (r = 0.32; P = 0.02), and furthermore, Axl transcript numbers were also higher in AML with high CD34 expression (n = 38, r = 0.42; P = 0.008). No significant difference between leukemias expressing and not expressing Axl was found with regard to complete remission rate. However, quantitative Axl expression was associated with worse progression-free and overall survival. Higher Axl levels had worse prognosis for progression-free (beta: 0.68, s.e.: 0.28, P = 0.015) and overall survival (beta: 0.61, s.e.: 0.31, P = 0.05) using multivariate Cox models adjusted for age, Auer rods and leukocyte counts. In conclusion, in this retrospective analysis, no difference with regard to clinical characteristics at diagnosis was found between AML patients whose leukemia cells show Axl expression vs patients whose cells are Axl negative. The association between Axl and bcl-2 and Axl and CD34 expression in de novo AML needs further investigation. Similarly, the negative impact of Axl levels on outcome should be confirmed in a larger cohort.

Acute Disease↗
PubMed1999

Factors affecting the outcome of allogeneic bone marrow transplantation for adult patients with refractory or relapsed acute leukaemia.

We evaluated the outcome of allogeneic bone marrow transplantation (BMT) for advanced acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) in 383 adult patients in nine Australian adult BMT centres between 1981 and 1997. The median overall survival for the group was 4.8 months, with an estimated 5-year survival of 18%. 28% of patients died of transplant-related toxicities within the first 100 d. Progressive disease was responsible for 48% of deaths. Multi-factor analysis demonstrated that AML (v ALL), disease status (second complete remission [CR2] v others), age (< 40 years) and duration of prior first complete remission (CR1) (> 6 months) were pre-transplant variables significantly associated with improved survival. Acute graft-versus-host disease (GVHD) of any grade reduced the rate of relapse in both AML and ALL, but only grades I-II were associated with improved survival. Both limited and extensive chronic GVHD were associated with increased survival. Only patients with AML in untreated first relapse or CR2, with a duration of CR1 > 6 months, or patients with T ALL, had a 5-year survival > 20%. Transplants for AML in induction failure or pre-B ALL in untreated first relapse or CR2 had an intermediate outcome, with 5-year survival of 10-20%. A 5-year survival of < 10% was observed for patients transplanted for ALL in induction failure or for pre-B ALL or AML in refractory first relapse or beyond CR2. These results suggest that for most adult patients with advanced acute leukaemia an allograft offers only a small chance of cure.

Adolescent↗
PubMed1999

The KID Study V: the natural history of type 2 diabetes in younger patients still practising a profession. Heterogeneity of basal and reactive C-peptide levels in relation to BMI, duration of disease, age and HbA1.

In a detailed evaluation of the data accumulated for 493 type 2 diabetics who participated in the KID Study, pre- and postprandial C-peptide was correlated with blood glucose level, HbA1, body mass index (BMI), duration of disease and age. As described earlier the KID-Study examined a younger cohort of type 2 diabetics predominately practising a profession. Our investigations demonstrate a significant increase of pre- as well as postprandial C-peptide levels with increasing obesity. However, delta C-peptide, as an indicator at the reaction capacity of pancreatic secretion, decreases significantly and continuously. Pre- as well as postprandial C-peptide levels decrease significantly with up to 15-20 years duration of disease. The preprandial pancreatic secretion is usually even at a high normal level at such a late stage whereas the secretory reserve of normal or mildly overweight as well as of obese type 2 diabetics is more impaired. In contrast to patients with a BMI < 30, obese patients with a BMI > 30 will also develop impairment of basal insulin secretion over decades. The patient's age did not influence the pre- or postprandial insulin secretion. The quality of metabolic control as measured by the HbA1 has nearly exclusive impact on the secretory reserve capacity. Correlation with increasing HbA1 concentrations, the postprandial but not the preprandial C-peptide levels decreased significantly and continuously. Predictive factors for a deterioration in pancreatic function are in order of importance: the extent of obesity, the quality of metabolic control and only last the duration of diabetes. Fortunately, consistent diabetic care can have an impact on the first two.

Age of Onset↗
PubMed1999

The KID Study VI: diabetic complications and associated diseases in younger type 2 diabetics still performing a profession. Prevalence and correlation with duration of diabetic state, BMI and C-peptide.

A sub-study evaluated 698 younger (54.5 +/- 6.9 years) type 2 diabetics of the KID Study participants to establish the prevalence of diabetic complications and associated diseases and their correlation with body mass index (BMI), duration of disease and to C-peptide levels. Only 19.8% of the type 2 diabetics had a normal weight. In all weight subgroups, the average age of diabetes manifestation were around age 45. In 46.6% of all type 2 diabetics we could already demonstrate microangiopathic complications. Strikingly, 15.9% of the patients already had proliferative retinopathies and 12.6% had albuminuria of more than 1000 mg/dl. 74.7% of our type 2 diabetics presented with the well-known risk cluster of the metabolic syndrome: In every other patient, we found hypertension and/or hyperlipoproteinaemia. Accordingly, the prevalence of the macroangiopathic diabetic complications, coronary artery disease and peripheral vascular disease was 17.8%, which is high for a relatively young population with a mean age of 53.9 years and goes conform with recent literature (Lowel et al., 1999). An increase in BMI correlated significantly with deterioration of HbA1, a decrease in HDL cholesterol, an increase in triglycerides and with a higher prevalence of hypertension. The frequency of nephropathy increase significantly up to a BMI of 30-35 kg/m2. Retinopathies and polyneuropathies were associated with BMI but increased significantly with the duration of the diabetic state. In contrast to microangiopathic diabetic complications, there was already a high prevalence of nephropathy after a comparatively short duration of disease. The prevalence of hyperlipoproteinaemia and hypertension did not depend from the duration of diabetes. These concomitant diseases already were frequent early in the disease and did not increase with the duration of disease. However, there was a strong correlation between increasing hyperlipoproteinaemia and hypertension and higher C-peptide levels. We found no coincidence between C-peptide levels and microangiopathic diabetic complications.

Adult↗
PubMed1999

Initial experience with a new balloon-guided single lead catheter for internal cardioversion of atrial fibrillation and dual chamber pacing.

BACKGROUND: Based on the observation that internal cardioversion (IntCV) of atrial fibrillation is effective with electrodes in the right atrium and pulmonary artery, a new balloon-guided catheter and external defibrillation device with optional dual chamber pacing was evaluated. METHODS: IntCV was attempted in 27 patients (age: 57 +/- 10 years, duration: 14 +/- 18 months, left atrial diameter 56 +/- 8 mm) using a new defibrillation device (Alert, EP MedSystems, Inc., NJ, USA) that allows the delivery of biphasic shocks (0.5-15 J, variable tilt), atrial and ventricular pacing, and online signal recording. Pacing and defibrillation shocks were applied via a 7.5 Fr balloon-guided catheter (EP MedSystems, Inc.). Pacing, sensing, and triggering were established through the proximal atrial array and an electrode ring between both defibrillation arrays and a single ventricular electrode ring. Catheters were inserted from the antecubital vein. RESULTS: In 25 of 27 patients sinus rhythm was restored with a mean energy of 6.7 +/- 4.5 J. In five patients, atrial postshock pacing was required for bradycardia and atrial premature beats. The mean fluoroscopy time was 2.0 +/- 1.3 minutes. CONCLUSION: The high success rate, ease of application, and backup dual chamber pacing suggest that this system is an alternative to established methods of cardioversion. In certain indications, such as failure of prior external cardioversion and situations in which a standard pulmonary balloon catheter is needed, this system would be advantageous.

Atrial Fibrillation↗
PubMed1999

Identification and complementation of frameshift mutations associated with loss of cytadherence in Mycoplasma pneumoniae.

Mycoplasma pneumoniae cytadherence is mediated by a specialized, polar attachment organelle. Certain spontaneously arising cytadherence mutants (designated class I) lack HMW2, fail to localize the adhesin protein P1 to the attachment organelle, and exhibit accelerated turnover of proteins HMW1, HMW3, and P65. Insertional inactivation of hmw2 by Tn4001 results in a phenotype nearly identical to that of the class I mutants, suggesting that the latter may result from a defect in hmw2. In this study, the recombinant wild-type hmw2 allele successfully complemented a class I mutant when introduced by transposon delivery. Synthesis of recombinant HMW2 at wild-type levels resulted in reacquisition of hemadsorption and normal levels of HMW1, HMW3, and P65. Low-level production of HMW2 in some transformants resulted in only an intermediate capacity to hemadsorb. Furthermore, full restoration of HMW1 and P65, but not that of HMW3, was directly proportional to the amount of recombinant HMW2 produced, reflecting the importance of proper stoichiometry for certain cytadherence-associated proteins. The recombinant class I hmw2 allele did not restore cytadherence, consistent with a defect in hmw2 in this mutant. A frameshift was discovered in different oligoadenine tracts in hmw2 from two independent class I mutants. Finally, protein P28 is thought to be the product of internal translation initiation in hmw2. A transposon excision-deletion mutant produced a truncated HMW2 but no P28, consistent with this conclusion. However, this deletion mutant was hemadsorption positive, indicating that P28 may not be required for cytadherence.

Adhesins, Bacterial↗
PubMed1999

Long-acting psychotraumatic properties of a cardiac arrest experience.

OBJECTIVE: Progress in resuscitation medicine allows an increasing proportion of patients to survive an out-of-hospital cardiac arrest. However, little is known about long-term adaptation to the vital breakdown. The present study assessed the long-term prevalence and severity of emotional disability of cardiac arrest survivors and ascertained whether survivors suffer from recurrent and intrusive recollections of the cardiac arrest. METHOD: Follow-up analysis was performed on all cardiac arrest survivors discharged from the hospital over a 5-year interval (1990-1994) in a defined inner city and suburban area. From 118 initially hospitalized cardiac arrest survivors, 45 patients were discharged alive from the hospital. After a mean follow-up period of 39 months (range = 22-64), 25 patients exhibited sufficient cerebral performance for psychodiagnostic assessment; 21 patients were assessed. RESULTS: Despite an impaired ability to concentrate, cardiac arrest survivors had levels of psychological adjustment at follow-up that were similar to those of 35 cardiac patients whose clinical course was not complicated by cardiac arrest. However, the diagnosis of psychotraumatic symptoms in cardiac arrest survivors led to a sharp separation between favorable and nonfavorable outcome in affective regulation and level of functioning. Of the cardiac arrest patients, those with high scores of intrusion and avoidance (N = 8) reported an enduring sense of demoralization with significantly more somatic complaints, depression, anxiety, lack of confidence in the future, and narrowing of social activities than those with low scores (N = 11). Long-acting sedation at illness onset significantly predicted a favorable outcome. CONCLUSIONS: This study provides the first empirical evidence that the application of the posttraumatic stress disorder paradigm in the long-term evaluation of cardiac arrest survivors significantly contributes to defining a patient population at high risk for serious emotional disability.

Adaptation, Psychological↗
PubMed1999

Antithrombogenic coating of stents using a biodegradable drug delivery technology.

To reduce the thrombogenic properties of coronary artery stents, a biodegradable polylactic acid (PLA) stent coating with an incorporated thrombin inhibitor and a platelet aggregation inhibitor has been developed. In an ex vivo human stasis model, its effect on platelets, plasmatic coagulation and its release characteristics were studied using whole blood. Bare steel and bare gold-surface stents were compared to steel and gold-surface stents coated with PLA (30 kDa) containing 5% polyethyleneglycol (PEG)-hirudin and 1% iloprost, with an empty tube as control. Markers of activated coagulation (prothrombin fragment F1-2 and thrombin-antithrombin III complex, TAT), were assayed and the release of drugs from the coating was assessed by aPTT and collagen-induced platelet aggregation. Bare steel and gold stents were completely covered by a blood clot, and high levels of coagulation markers (F1-2 fragment and TAT) were detected. No differences in the thrombogenic properties were found between bare gold or steel stents. Coated stents were free of blood clots and only minor elevations of markers were detected. Release data from in-vitro studies over 90 days showed a gradual release of the drugs with an initial exponential release characteristic for PEG-hirudin, slow release of iloprost and a 10% degradation of the PLA carrier. This drug releasing biodegradable coating effectively reduced thrombus formation independent of the metallic surface.

Antithrombins↗
PubMed1999

Yttrium-90 DOTATOC: first clinical results.

In a pilot study, DOTA-d-Phe(1)-Tyr(3)-octreotide (DOTATOC), which can be labelled with the beta-emitting radioisotope yttrium-90, has recently been used for the treatment of patients with advanced somatostatin receptor-positive tumours who had no other treatment option. The aim of the present study was to elucidate the therapeutic potential of (90)Y-DOTATOC in a larger number of patients employing a standardized treatment protocol. Careful attention was paid to any side-effects (renal and/or haematological toxicity). Of 44 patients with advanced somatostatin receptor-positive tumours of different histology, 29 could be included in the study. The 15 patients who were excluded from the study protocol were assigned to our institution for purely compassionate reasons. The 29 patients who were included received four or more single doses of (90)Y-DOTATOC with ascending activity at intervals of approximately 6 weeks (cumulative dose 6120+/-1347 MBq/m(2)) with the aim of performing an intra-patient dose escalation study. In total, 127 single treatments were given. In eight of these 127 single treatments, total doses of > or = 3700 MBq were administered. In an effort to prevent renal toxicity, two patients received Hartmann-Hepa 8% solution during all therapy cycles, while 13 patients did so during some but not all therapy cycles; in 14 patients no solution was administered during the therapy cycles. The treatment was monitored by computed tomography and indium-111 DOTATOC scintigraphy. Blood parameters were controlled weekly, while tumour markers and liver enzymes were controlled 6-weekly. Of the 29 patients, 24 patients showed no severe renal or haematological toxicity (toxicity < or = grade 2 according to the National Cancer Institute grading criteria). These 24 patients received a cumulative dose of < or = 7400 MBq/m(2). Five patients developed renal and/or haematological toxicity. All of these five patients received a cumulative dose of >7400 MBq/m(2) and had received no Hartmann-Hepa 8% solution during the therapy cycles. Four of the five patients developed renal toxicity; two of these patients showed stable renal insufficiency and two require haemodialysis. Two of the five patients exhibited anaemia (both grade 3) and thrombopenia (grade 2 and 4, respectively). To date, 20 of the 29 patients have shown a disease stabilization, two a partial remission, four a reduction of tumour mass <50% and three a progression of tumour growth. (90)Y-DOTATOC could be a powerful and promising new therapeutic agent for anti-cancer treatment - at least in terms of an adjuvant starting point of the disease. However, problems with toxicity have to be solved. Evaluation of the effect of amino acid infusions (e.g. Hartmann-Hepa 8% solution) during (90)Y-DOTATOC treatments with the aim of reducing renal toxicity is ongoing.

Adult↗
PubMed1998

A phase I study of adenovirus-mediated wild-type p53 gene transfer in patients with advanced non-small cell lung cancer.

Mutations of the tumor suppressor gene p53 are the most common genetic alterations observed in human cancer. Loss of wild-type p53 function impairs cell cycle arrest as well as repair mechanisms involved in response to DNA damage. Further, apoptotic pathways as induced by radio- or chemotherapy are also abrogated. Gene transfer of wild-type p53 was shown to reverse these deficiencies and to induce apoptosis in vitro and in preclinical in vivo tumor models. A phase I dose escalation study of a single intratumoral injection of a replication-defective adenoviral expression vector encoding wild-type p53 was carried out in patients with incurable non-small cell lung cancer. All patients enrolled had p53 protein overexpression as a marker of mutant p53 status in pretreatment tumor biopsies. Treatment was performed either by bronchoscopic intratumoral injection or by CT-guided percutaneous intratumoral injection of the vector solution. Fifteen patients were enrolled in two centers, and were treated at four different dose levels ranging from 10(7) to 10(10) PFU (7.5 x 10(9) to 7.5 x 10(12) particles). No clinically significant toxicity was observed. Successful transfer of wild-type p53 was achieved only with higher vector doses. Vector-specific wild-type p53 RNA sequences could be demonstrated in posttreatment biopsies of six patients. Transient local disease control by a single intratumoral injection of the vector solution was observed in four of those six successfully transduced patients. There was no evidence of clinical responses at untreated tumor sites. Wild-type p53 gene therapy by intratumoral injection of a replication-defective adenoviral expression vector is safe, feasible, and biologically effective in patients with advanced non-small cell lung cancer.

Adenoviridae↗
PubMed1998

The subunit b of the F0F1-type ATPase of the bacterium Mycoplasma pneumoniae is a lipoprotein.

The DNA sequence analysis of the F0F1-ATPase operon of the bacterium Mycoplasma pneumoniae predicted that the subunit b, encoded by the gene atpF, is a lipoprotein of the murein lipoprotein type of Escherichia coli. Here we experimentally verify this prediction by metabolic labeling of subunit b with [14C]palmitic acid and by in vivo interfering with the processing of the prolipoprotein form of subunit b by the antibiotic globomycin, a specific inhibitor of the signal peptidase II. Our results suggest that the subunit b of the F0F1-ATPase of M. pneumoniae is anchored at the cytoplasmic membrane by an N-terminal lipid modification in addition to its transmembrane domain. The lipoprotein nature of subunit b and its proposed membrane topology seems to be characteristic for mycoplasmas, since among all sequenced bacterial atpF genes, only those from Mycoplasma gallisepticum and Mycoplasma genitalium code for a conserved lipoprotein consensus sequence.

Amino Acid Sequence↗
PubMed1998

[ 40 years of 5-fluorouracil--still an attractive cytostatic].

On its 40th birthday 5-fluorouracil (FU) is still an attractive drug frequently employed in adjuvant and palliative treatment of colorectal and breast cancer, head and neck cancer, oesophageal cancer and anal cancer. After all this time it is still not known what the optimal schedule or the best form of administration is, and whether or not modulation of the drug is of any benefit. This article deals with the drug's different modes of action depending on the schedule of administration. An overview of the literature on drug modulation is given. We introduce the less well-known side effects of the drug and the newly developed orally administered prodrugs of FU.

Antimetabolites, Antineoplastic↗
PubMed1998

A depressant insect-selective toxin analog from the venom of the scorpion Leiurus quinquestriatus hebraeus--purification and structure/function characterization.

The scorpion venom-derived excitatory and depressant insect-selective polypeptide neurotoxins modify sodium conductance in insect neuronal membranes and differ greatly in their primary structures and symptoms induced in blow fly larvae. We report here the purification and characterization of a new insect selective toxin, LqhIT5. LqhIT5 is more similar to the excitatory toxins in its mode of action and the depressant toxins in its primary structure. This toxin is a single polypeptide composed of 61 amino acids that are cross linked by four disulfide bonds. When LqhIT5 is injected into blow fly larvae, a fast contraction paralysis occurs without depressant activity. No mammalian toxicity was detected by subcutaneous or intracranial injections of this toxin into mice. Sequence comparison of LqhIT5 and known depressant toxins shows a high degree of similarity among the amino acids located on the C-terminus of the toxins. However, there are some clear differences in the amino acids located close to the N-terminus of the toxins. By the aid of homology modeling, we demonstrated that these amino acids have the same orientation in the tertiary structure of the molecule and are exposed to the environment. The change in the mode of action of LqhIT5 (no depressant activity) by substitutions of a few amino acids located on a specific exposed area of the toxin shed a new light on the structure/function relationship of scorpion toxins. These results caution that similarity in the mechanism of action of scorpion toxins does not always follow from an overall similarity in sequence.

Amino Acid Sequence↗