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Biomedical subjects

H Ludwig

Publications and source records attributed to H Ludwig.

At least 55 records · Page 3Linked to original sources
PubMed2001

Transcription of glycolytic genes and operons in Bacillus subtilis: evidence for the presence of multiple levels of control of the gapA operon.

Glycolysis is one of the main pathways of carbon catabolism in Bacillus subtilis. Although the biochemical activity of glycolytic enzymes has been studied in detail, no information about the expression of glycolytic genes has so far been available in this organism. Therefore, transcriptional analysis of all glycolytic genes was performed. The genes cggR, gapA, pgk, tpi, pgm and eno, encoding the enzymes required for the interconversion of triose phosphates, are transcribed as a hexacistronic operon as demonstrated by Northern analysis. This gapA operon is repressed by the regulator CggR. The presence of sugars and amino acids synergistically results in the induction of the gapA operon. The transcriptional start site upstream of cggR was mapped by primer extension. Transcripts originating upstream of cggR are processed near the 3' end of cggR. This endonucleolytic cleavage leads to differential stability of the resulting processing products: the monocistronic cggR message is very rapidly degraded, whereas the mRNA species encoding glycolytic enzymes exhibit much higher stability. An additional internal constitutive promoter was identified upstream of pgk. Thus, gapA is the most strongly regulated gene of this operon. The pfk pyk operon encoding phosphofructokinase and pyruvate kinase is weakly induced by glucose. In contrast, the genes pgi and fbaA, coding for phosphoglucoisomerase and fructose-1,6-bisphosphate aldolase, are constitutively expressed.

Bacillus subtilis↗
PubMed2001

Subgaleal versus subperiosteal dissection in fronto-orbital advancement procedures.

Extensive cranioorbital surgery for craniosynostosis in young children can produce excessive blood loss. Thus, to overcome the disadvantage of unappropriated blood loss and translocation of the osteosynthesis material, we performed a subgaleal dissection in infants and compared the subperiosteal with the subgaleal surgical approach in 29 children who underwent surgery for craniosynostosis. The treatment goal of correction of the deformity was accomplished in each case. Fronto-orbital deformities were significantly improved in all patients. Blood loss was less in the group with subgaleal elevation of the forehead (mean = 163 ml) compared with the subperiosteal group, which had a mean 266 ml blood loss. The subgaleal dissection caused less bleeding and tethering of the advanced bone.

Blood Loss, Surgical↗
PubMed2001

[Bumm, Zweifel, Kubli and others--examples of the academic interlacing between Switzerland and Germany].

There is an interlacing in academic gynecology and obstetrics between Germany and Switzerland which leads back to the founding years of both societies. Germans have been elected to the chairs in Zürich, Bern, and Basel, whereas Swiss have been appointed to Erlangen, Leipzig, Dresden, and Frankfurt. Reservations from both sides, if any, were not prevailing. Even if the balance at present might show a trend again towards the Germans being chairmen at German-speaking Swiss Universities, the historical line contradicts the impression of one-sidedness. It is the academic exchange followed by a remarkable interlacing between the two German-speaking nations which will certainly continue into the future, all the more so in a Europe where historical differences are more or less overcome. The younger generation will extend and improve the links already laid down in the past. The men mentioned above have all been leading figures during their time, Fred Kubli so in particular. They will be followed by successors. Might they be as excellent as their predecessors have been.

Germany↗
PubMed2000

Deletion of 13q14 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization.

Interphase fluorescence in situ hybridization (FISH) studies of chromosomal region 13q14 were performed to investigate the incidence and clinical importance of deletions in multiple myeloma (MM). Monoallelic deletions of the retinoblastoma-1 (rb-1) gene and the D13S319 locus were observed in 48 of 104 patients (46.2%) and in 28 of 72 (38.9%) patients, respectively, with newly diagnosed MM. FISH studies found that 13q14 was deleted in all 17 patients with karyotypic evidence of monosomy 13 or deletion of 13q but also in 9 of 19 patients with apparently normal karyotypes. Patients with a 13q14 deletion were more likely to have stage III disease (P =.022), higher serum levels of beta(2)-microglobulin (P =.059), and a higher percentage of bone marrow plasma cells (P =.085) than patients with a normal 13q14 status on FISH analysis. In patients with a deletion of 13q14, myeloma cell proliferation (Ki-67) was markedly increased (22.0% +/- 6.9% compared with 15.6% +/- 8.2% in patients without the deletion; P =.0008). Evaluation of bromodeoxyuridine incorporation in 5 patients revealed that both rb-1-deleted and rb-1-normal MM subpopulations were proliferative. The presence of a 13q14 deletion on FISH analysis was associated with a significantly lower rate of response to conventional-dose chemotherapy (40.8% compared with 78. 6%; P =.009) and a shorter overall survival (24.2 months compared with > 60 months; P <.005) than in patients without the deletion. Multivariate analysis of prognostic factors confirmed the independent predictive value of 13q14 deletions for shortened survival. In conclusion, deletions of 13q14 are frequently detected by interphase FISH in patients with newly diagnosed MM, correlate with increased proliferative activity, and represent an independent adverse prognostic feature in MM. (Blood. 2000;95:1925-1930)

Adult↗
PubMed2000

Interferon-alpha treatment in multiple myeloma: meta-analysis of 30 randomised trials among 3948 patients.

BACKGROUND: After two decades of interferon (IFN) treatment in myeloma patients and many randomised clinical trials, no definite proof of its benefits exists. This meta-analysis of all available relevant published data tests the differences between IFN and control arms in a large patient population and addresses the issue of cost-effectiveness. PATIENTS AND METHODS: Meta-analysis was performed on 17 trials among 2333 patients who received IFN-chemotherapy induction treatment or chemotherapy alone and on 13 trials among 1615 patients on IFN maintenance therapy or without treatment. Response rates and parameters of published Kaplan Meier relapse-free and overall survival curves were analysed. RESULTS: Patients in IFN arms showed significantly better results in all investigated parameters: IFN-chemotherapy induction treatment yielded 6.6% higher response rates (2P < 0.002) as well as 4.8-month and 3.1-month prolongations of relapse-free (P < 0.01) and overall survival (P < 0.01), respectively. Interferon maintenance therapy lead to 4.4-month (P < 0.01) and 7.0-month (P < 0.01) prolongations of relapse-free and overall survival, respectively. Meta-analysis of all IFN trials combined resulted in 4.6-month and 3.7-month IFN-related gains in relapse-free and overall survival, respectively. As early as 6 and 12 months after the start of IFN treatment, percentages of cumulative relapse-free and overall survival were always significantly higher in IFN trial arms. IFN drug expenses for a one-year survival gain, as determined from AUCs of best-fitted Gompertz functions of IFN and control survival curves, were estimated to be US$42,482.28 for induction therapy and US$18,968.16 for maintenance treatment. CONCLUSIONS: Significantly superior outcomes were consistently found in IFN trial arms by meta-analysis of published data. These results are in accordance with a concomittantly conducted meta-analysis on individual patient data but were much easier to accrue. Taking all our results into account. i.e., the consistently significant, although limited, improvement of clinical outcomes and its acceptable cost-effectiveness, IFN treatment of patients with multiple myeloma seems worthwhile to be considered.

Cost-Benefit Analysis↗
PubMed2000

Amantadine in depressive patients with Borna disease virus (BDV) infection: an open trial.

OBJECTIVE: Originally introduced into pharmacotherapy as an antiviral compound, amantadine was shown to also have multiple pharmacological eftfects on the central nervous system. In addition. only a few studies reported on certain antidepressive properties of amantadine. This effect was highlighted by the discovery of its antiviral effect on Borna disease virus (BDV), which is hypothesized to be an etiopathogenetic factor to subtypes of affective disorders. Therefore, the therapeutical use of amantadine in BDV-infected depressive patients was investigated. METHODS: In this open trial, amantadine was added to antidepressive and or mood-stabilizing compounds treating BDV-infected depressed patients (n = 25) with bipolar or major depressive disorders. Amantadine was given twice a day (100-300 mg/day) for a mean of 11 weeks. Antidepressive treatment response was measured on the Hamilton rating scale for depression (HAM-D) and/or with an operationalized diagnostic criteria system (OPCRIT: version 3.31). Virological response was measured by expression of BDV infection parameters in blood samples. RESULTS: The overall response rate of the amantadine augmentation in the BDV-infected patients with regard to depressive symptoms was 68% after a mean of 2.9 weeks of treatment. Bipolar I patients improved faster and did not show any following hypomania. In addition, the decrease of depression tended to correspond with the decrease in viral activity. CONCLUSION: Amantadine appears to show a remarkable antidepressive efficacy in BDV-infected depressive patients. The antidepressive effect in this open trial appeared to be comparable to standard antidepressives, possibly being a result of its antiviral effect against BDV as a potentially relevant etiopathogenetic factor in these disorders.

Adult↗
PubMed2000

Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a hereditary microangiopathic condition causing stroke in young adults. The responsible gene has recently been identified as the Notch3 gene. Notch3 encodes a large transmembrane receptor with 34 extracellularly localised epidermal growth factor-like (EGF) repeat domains. We screened 71 unrelated CADASIL families for mutations in two exons coding for the first five EGF-like repeats and found mutations in 70% of the families (n = 50). Two types of mutations were identified: 48 families (96%) had missense mutations and two families (4%) had small in-frame deletions. Seven mutations occurred multiple times. All of them are C to T transitions that affect CpG dinucleotides, suggesting that their multiple occurrence is due to the hypermutability of this sequence. All mutations, including the two deletions, result in the gain or loss of a cysteine residue, thus substantiating the pivotal role of an uneven number of cysteine residues within EGF-like repeat domains of Notch3 in the pathogenesis of CADASIL. To study the potential effects of these mutations 3D homology models of the first six EGF domains were generated on the basis of NMR data from human fibrillin-1. These models predict domain misfolding for a subset of mutations.

Amino Acid Sequence↗
PubMed2000

Deletions of chromosome 13q in monoclonal gammopathy of undetermined significance.

Since deletion of chromosome 13q is a clinically relevant feature in multiple myeloma (MM), we analyzed bone marrow plasma cells from 29 patients with monoclonal gammopathy of undetermined significance (MGUS) to investigate the chromosome 13 status in MGUS. Studies were performed by interphase fluorescence in situ hybridization (FISH) with a panel of 13q14-specific probes (RB1, D13S319, D13S25, D13S31). Plasma cells with a deletion of at least one of the 13q14 loci were detected in 13 patients (44.8%) with MGUS. In five patients (17.2%), deletions of all four 13q14-specific probes were observed, and the additional deletion of a 13q telomeric region (D13S327) suggested loss of the entire 13q arm or monosomy 13. Loss of 13q14 was observed to be monoallelic and to occur in 11.0 to 35.0% of plasma cells (cut-off levels for a deletion <10% with all probes). Nine of 17 patients (52.9%) with MM progressing from a pre-existing MGUS had evidence for a deletion of 13q14 as determined by FISH with the RB1 probe. These results suggest that deletion of 13q14 is an early event in the development of monoclonal gammopathies, but its role for the eventual progression to MM remains to be determined prospectively.

Adult↗
PubMed2000

Interferon in multiple myeloma--summary of treatment results and clinical implications.

Even though interferon (IFN) has been used in myeloma treatment for more than two decades, its efficacy is still controversial. Meta-analysis of randomized trials is based either on individual patient data or on published data. We performed meta-analyses on published and reported data using, in addition to the standard method, three independent methods of evaluating Kaplan-Meier curves. Thirty randomized trials on IFN induction or maintenance treatment were meta-analyzed. Combined IFN-chemotherapy induction treatment resulted in significant increases of repsonse rates (6.6%), as well as median relapse-free (4.8 months) and overall survival (3.1 months). IFN maintenance treatment prolonged median relapse-free survival by 4.4 months, median overall survival by 7.9 months. Drug costs of IFN per 1-year survival gain were US$ 42,236.19 for induction therapy and US$ 18,114.95 for maintenance treatment. To conclude, our results a are in accordance with those obtained from individual patient data by the Myeloma Trialists' Collaborative Group. Because of the consistent, though limited, improved trial outcomes, IFN treatment should be suggested to all myeloma patients who might benefit from it.

Antineoplastic Agents↗
PubMed2000

Cerebrovascular tone rather than intracranial pressure determines the effective downstream pressure of the cerebral circulation in the absence of intracranial hypertension.

Cerebral perfusion pressure is commonly calculated from the difference between mean arterial pressure and intracranial pressure because intracranial pressure is known to represent the effective downstream pressure of the cerebral circulation. Studies of other organs, however, have shown that effective downstream pressure is determined by a critical closing pressure located at the arteriolar level. This study was designed to investigate the effects of PCO2-induced variations in cerebrovascular tone on the effective downstream pressure of the cerebral circulation. Sixteen patients recovering from head injury were studied. Intracranial pressure was assessed by epidural pressure transducers. Blood flow velocity in the middle cerebral artery was monitored by transcranial Doppler sonography. Effective downstream pressure was derived from the zero flow pressure as extrapolated by regression analysis of instantaneous arterial pressure/middle cerebral artery flow velocity relationships. PaCO2 was varied between 30 and 47 mm Hg in randomized sequence. Intracranial pressure decreased from 18.5+/-5.2 mm Hg during hypercapnia to 9.9+/-3.1 mm Hg during hypocapnia. In contrast, effective downstream pressure increased from 13.7+/-9.6 mm Hg to 23.4+/-8.6 mm Hg and exceeded intracranial pressure at hypocapnic PaCO2 levels. Our results demonstrate that, in the absence of intracranial hypertension, intracranial pressure does not necessarily represent the effective downstream pressure of the cerebral circulation. Instead, the tone of cerebral resistance vessels seems to determine effective downstream pressure. This suggests a modified model of the cerebral circulation based on the existence of two Starling resistors in a series connection.

Adult↗
PubMed2000

Predictive role of interphase cytogenetics for survival of patients with multiple myeloma.

PURPOSE: Recent metaphase cytogenetic studies suggested that specific chromosomal abnormalities are of prognostic significance in patients with multiple myeloma (MM). Because the true incidence of chromosomal abnormalities in MM is much higher than that detected by metaphase analysis, we used interphase fluorescence in situ hybridization (FISH) to determine the prognostic value of specific chromosomal aberrations. PATIENTS AND METHODS: Bone marrow plasma cells from 89 previously untreated patients with MM were studied consecutively by FISH to detect the deletions of 13q14, 17p13, and 11q and the presence of t(11;14)(q13;q32). FISH results were analyzed in the context of clinical parameters (response to treatment and survival after conventional-dose chemotherapy), and a multivariate analysis of prognostic factors was performed. RESULTS: By FISH, the deletion of 13q14 occurred in 40 patients (44.9%), deletion of 17p13 in 22 (24.7%), and 11q abnormalities in 14 (15.7%; seven with t(11;14)). Deletions of 13q14 and 17p13 were associated with poor response to induction treatment (46.9% v 77.3% in those without deletions, P =.006 and 40.0% v 73.2%, P =.008, respectively) and short median overall survival (OS) time (24.2 v 88.1 months, P =. 008 and 16.2 v 51.3 months, P =.008, respectively). Short median OS time was also observed for patients with 11q abnormalities (13.1 v 41.6 months, P =.02). According to the number of unfavorable cytogenetic features (deletion of 13q14, deletion of 17p13, and aberrations of 11q) that were present in each patient (0 v 1 v 2 or 3), patients with significantly different OS times could be discriminated from one another (102.4 v 29.6 v 13.9 months, P <.001, respectively). CONCLUSION: For patients with MM who were treated with conventional-dose chemotherapy, interphase FISH for 13q14, 17p13, and 11q provides prognostically relevant information in addition to that provided by standard prognostic factors. This observation may be considered for risk-adapted stratifications of MM patients in future clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Borna disease virus: new aspects on infection, disease, diagnosis and epidemiology.

A 'disease of the head' affecting horses, as described in the 17th Century is now known as Borna disease. Research over the past 100 years has established that the aetiological agent, Borna disease virus (BDV), is an unsegmented, single- and negative-stranded, enveloped ribonucleic acid (RNA) virus which represents the family Bornaviridae in the order Mononegavirales. The virus exists world-wide in horses, sheep, cattle, cats, dogs and ostriches. The infection can be fatal, but the majority of carriers are persistently infected without showing symptoms. The association with psychiatric diseases in humans led to an international explosion of research on BDV, with centres established in Germany, the United States of America and Japan. Experimental infections of tree shrews and rats served to examine the effects of persistent and overt disease, most excitingly, virus-induced behavioural changes, and emotional and learning deficits. This 'emerging' virus infection shows complex pathogenetic mechanisms in the nervous system, but also spreads through myelo-monocytic cells. Diagnosis can be made serologically, but detection of antigen markers in peripheral white blood cells, combined with nucleic acid amplification is more profitable. Comparative RNA studies reveal an unusually high genetic homology of viruses. Isolates recovered from humans and equines suggest species-specificity. Vaccination is not an advisable strategy, but antiviral therapy, especially with amantadine sulphate, promises efficacy in human mood disorders, and is effective in vitro. Infections with BDV follow a vulnerability principle to cause disease. Although cross-species transmission of this commensal virus has not been proven, zoonotic aspects of BDV should be carefully considered.

Animals↗
PubMed2000

[Relevance of infection with equine herpesvirus 1 (EHV-1) in a German thoroughbred stud: vaccination, abortion and diagnosis].

The aim of the present study was to clarify whether an EHV-1 induced abortion can be prognosticated by an increase of antibody titres, virus shedding and/or viraemia and whether the current abortion diagnostic is suitable. In this context the immune response post immunization and a possible reactivation were of great interest. For this purpose blood samples of 32 mares between the ages of 5-21 years were regularly investigated during a period of two years before and after vaccination and pregnancy. Neutralization tests, indirect immunofluorescence tests as well as PCR and virus isolation were used for EHV-1 diagnostics. It could be shown that the horses reacted individually to vaccination. In 14 cases a EHV-1-reactivation was suggested. An abortion prognosis was not possible even using serological, virological and molecular biological parameters. In addition, virus shedding and antibody titres were individual. An acute infection was detectable by a significant rise of antibodies and viraemia as well as virus shedding in the secretions. For the abortion diagnostics the antigen detection in combination with virus isolation and PCR from fetal lungs gave reliable results. In addition, the virological and serological investigation of the mare is recommendable. For prophylaxis we would advise a regular vaccination and strict hygiene.

Abortion, Veterinary↗
PubMed1999

Quantitative MRI in CADASIL: correlation with disability and cognitive performance.

OBJECTIVE: To study correlations between total lesion load on brain MRI and clinical features, and to evaluate the influence of demographic variables on quantitative MRI variables in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). BACKGROUND: CADASIL is a hereditary form of small-vessel disease caused by mutations within the Notch3 gene. MRI abnormalities have been found both in asymptomatic and symptomatic CADASIL individuals. METHODS: Quantitative measurements on cerebral MRI were performed in 64 CADASIL individuals. MRI lesions were quantified using a semi-automated segmentation technique based on local thresholds. RESULTS: MRI total lesion volume correlated significantly with disability (Rankin Scale) on both T1- and proton density (PD)-weighted images. There was a significant inverse correlation between total lesion volume and overall cognitive performance as determined by the Mini-Mental State Examination. Age but not sex was correlated with lesion load both on T1- and PD-weighted images. There was no detectable influence of the Notch3 genotype on quantitative MRI variables. CONCLUSIONS: This study demonstrates correlations between MRI lesion volume and clinical characteristics in CADASIL. Longitudinal studies are now warranted to investigate whether quantitative MRI could be used as an adjunct outcome measure in future therapeutic trials in CADASIL.

Adult↗