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Michael Hoffmann

Publications and source records attributed to Michael Hoffmann.

17 recordsLinked to original sources
PubMed2006

Computational photochemistry of retinal proteins.

High spectral tunability and quantum yield are the striking features of rhodopsin photochemistry. They rely on a strong and complex interaction of their chromophore, the protonated Schiff base of retinal, with its protein environment. In this article, we review the progress in the computational modeling of these systems, focusing on the optical properties and the excited state dynamics. While the earlier success of atomistic theoretical models was based on the breakthrough in X-ray crystallography and combined quantum mechanical molecular mechanical (QM/MM) methodology, recent advances point out the importance of high-level QM methods and the incorporation of effects that are neglected in conventional QM/MM or ONIOM schemes, like polarization and charge transfer.

Computational Biology↗
PubMed2006

Color tuning in rhodopsins: the mechanism for the spectral shift between bacteriorhodopsin and sensory rhodopsin II.

The mechanism of color tuning in the rhodopsin family of proteins has been studied by comparing the optical properties of the light-driven proton pump bacteriorhodopsin (bR) and the light detector sensory rhodopsin II (sRII). Despite a high structural similarity, the maximal absorption is blue-shifted from 568 nm in bR to 497 nm in sRII. The molecular mechanism of this shift is still a matter of debate, and its clarification sheds light onto the general mechanisms of color tuning in retinal proteins. The calculations employ a combined quantum mechanical/molecular mechanical (QM/MM) technique, using a DFT-based method for ground state properties and the semiempirical OM2/MRCI method and ab initio SORCI method for excited state calculations. The high efficiency of the methodology has allowed us to study a wide variety of aspects including dynamical effects. The absorption shift as well as various mutation experiments and vibrational properties have been successfully reproduced. Our results indicate that several sources contribute to the spectral shift between bR and sRII. The main factors are the counterion region at the extracellular side of retinal and the amino acid composition of the binding pocket. Our analysis allows a distinction and identification of the different effects in detail and leads to a clear picture of the mechanism of color tuning, which is in good agreement with available experimental data.

Bacteriorhodopsins↗
PubMed2006

Safety pharmacology assessment of drug-induced QT-prolongation in dogs with reduced repolarization reserve.

INTRODUCTION: Drug-induced QT-prolongation, often based on hERG K+ current inhibition, has become a major safety concern during drug development. Hence, regulatory guidelines require combined in vitro and in vivo assays to assess the potential of new chemical entities to delay ventricular repolarization. Here, results of a pharmacological validation study with the torsadogenic compound sotalol are presented. METHODS: Alteration of ECG parameters was investigated in both conscious and anesthetized Beagle dogs (cumulative infusions of D,L-sotalol; n=6). The repolarization reserve of the latter was reduced by neurolept anesthesia using the hERG blocker droperidol (0.25 mg/kg/h yielding mean plasma concentrations of 0.5 microM). Furthermore, hERG K+ current and action potentials (AP; rabbit Purkinje fibers) were measured in vitro. RESULTS: The Fridericia corrected QT interval, QTcF, in conscious dogs (control: 254+/-15 ms), was dose-dependently prolonged by D,L-sotalol (+42 ms at plasma levels of 261 microM; dose 30 mg/kg). In anesthetized dogs, baseline QTcF (337+/-35 ms) was already prolonged compared to conscious dogs. In addition, QTcF-increase (+90 ms) was more pronounced at lower D,L-sotalol plasma levels (181 microM; dose 10 mg/kg), and proarrhythmic markers Tpeak-Tend and short term variability of QT were increased. These in vivo findings are supported by in vitro data. The hERG K+ current was blocked by D,L-sotalol (IC50 approximately 1.2 mM, IC20 approximately 250 microM) and droperidol (IC50 approximately 0.1 microM, IC20 approximately 0.02 microM). Purkinje fiber APs were concentration-dependently prolonged by D,L-sotalol (APD90:+60% at 30 microM) and droperidol (APD90:+55% at 1 microM). Low droperidol concentrations increased the sensitivity of Purkinje fibers towards D,L-sotalol-mediated AP prolongation. DISCUSSION: In conclusion, the higher sensitivity of anesthetized dogs towards sotalol-induced QT-prolongation is due to a reduced cardiac repolarization reserve caused by the hERG blocker droperidol. Hence, the droperidol-/fentanyl-/N2O-anesthetized dog is a particularly sensitive animal model for the detection of drug-induced QT-prolongation in safety pharmacology studies.

Action Potentials↗
PubMed2006

Metacognition in stroke: bedside assessment and relation to location, size, and stroke severity.

BACKGROUND: Frontal syndromes are poorly represented on stroke scales, yet may constitute an important component of the neurologic deficit impacting treatment and rehabilitation efforts. AIMS: To validate an assessment of a frontal network syndrome score (FNSS) in stroke and to ascertain the relationship of the FNSS to lesion location, volume, and severity in young people with stroke. METHODS: Accrual through a cognitive stroke registry of young, alert, nonaphasic, nonencephalopathic, nonsubstance abuse prone people who were tested with the 16 domain FNSS within 4 weeks of their stroke. Lesion location was determined by the Cerefy 3-dimensional, digital, coxial brain atlas identifying 6 regions of cerebral interest. Lesion severity was assessed by the National Institute of Health Stroke Score and infarct volume was measured in cubic centimeters. RESULTS: From a sample of 456 cases in the registry after exclusions of encephalopathy, depression, and aphasia, cases with frontal network syndrome encompassed 132 of 341 persons (39%). Of these patients (n=80) with mean age 45.7 years [confidence interval (CI): 43.4, 48.1], educational level 13.1 years (CI:12.5, 13.6), mean National Institute of Health Stroke Score of 3.3 (CI: 2.6, 4.0), and mean lesion volume 30.3 mL (CI: 13.7, 46.9), had full testing with the FNSS battery yielding sensitivity (93%), specificity (74%), positive predictive value (79%), negative predictive value (90%), and a good interrater reliability (kappa=0.89, P=0.001). Construct validity testing with 15 frontal neuropsychologic tests revealed good to excellent significant Pearson r values in 14 of 15 of the tests. There was no correlation (Pearson's) for lesion volume (r=0.07, P=0.52) but significant correlation with stroke severity (r=0.23, P=0.03). Analysis of variance testing of the FNSS revealed significant differences for all 6 domains without intergroup significant differences for frontal network syndrome domains in the stroke group. CONCLUSIONS: The FNSS is a valid, practical measure of frontal syndromes in stroke. Frontal syndromes are common in young people with stroke and may be present no matter where the lesion, are not dependent on size of stroke and have a low correlation with stroke severity.

Adolescent↗
PubMed2006

Stroke and chest pain in young people with migraine.

BACKGROUND: Cerebrovascular and cardiovascular complications in migraineurs may be part of the migraine process and also consequent to triptan treatment. AIM: To determine the frequency, subtypes and associations of migraine-associated stroke and angina in young people (18-49 years). METHODS: Patients were derived from a tertiary referral migraine and stroke registry. Migraine-associated stroke was classified according to the four groups described by Welch and by the TOAST etiological stroke classification. A clinical description of angina during a migraine attack was required for the diagnosis of cardiac migraine without concomitant triptan or other vasoactive medications. RESULTS: Of the young patients with stroke (349/1316; 26.5%), there were 30 (30/349; 8.6%) who had migraine at the time of stroke when categorized by the Welch classification type II to IV (type II n = 5, type III n = 2, type IV n = 3). Comparison of type I (n = 20) versus types II-IV (n = 10) showed significant difference (P = .03). Topographically the lesions were distributed into the partial anterior circulation (n = 8) and posterior circulation (n = 2) (P = .04). Comparison of anterior and posterior circulation territories of infarction indicated significant difference (n = 26/30 and 4/30; P = .01). The stroke etiological subtypes included cardiogenic (n = 5), atherogenic (n = 15), other (n = 5), and unknown (n = 5), with none diagnosed with small-vessel cerebrovascular disease. Traditional stroke mechanistic entities (cardiac and atherogenic) differed significantly in comparison to the other and unknown categories P = .05. Cardiovascular patients with angina during a migraine attack (n = 9/1040; 0.9%), included IHS subtypes; migraine without aura (n = 4), migraine with aura (n = 4), and complicated migraine (n = 1). One patient required cardiac catheterization on account of significant ECG changes, with documented, reversible vasospasm. CONCLUSION: (i) Migraine-induced stroke remains controversial, with only two probable cases of type Welch III A+B in a large registry. (ii) Cardiac migraine may be a distinct entity requiring careful differentiation from triptan-induced chest pain.

Adolescent↗
PubMed2005

Pinpointing and preventing imminent extinctions.

Slowing rates of global biodiversity loss requires preventing species extinctions. Here we pinpoint centers of imminent extinction, where highly threatened species are confined to single sites. Within five globally assessed taxa (i.e., mammals, birds, selected reptiles, amphibians, and conifers), we find 794 such species, three times the number recorded as having gone extinct since 1500. These species occur in 595 sites, concentrated in tropical forests, on islands, and in mountainous areas. Their taxonomic and geographical distribution differs significantly from that of historical extinctions, indicating an expansion of the current extinction episode beyond sensitive species and places toward the planet's most biodiverse mainland regions. Only one-third of the sites are legally protected, and most are surrounded by intense human development. These sites represent clear opportunities for urgent conservation action to prevent species loss.

Animals↗
PubMed2005

The value of the IUCN Red List for conservation.

The IUCN Red List of Threatened Species is the most comprehensive resource detailing the global conservation status of plants and animals. The 2004 edition represents a milestone in the four-decade long history of the Red List, including the first Global Amphibian Assessment and a near doubling in assessed species since 2000. Moreover, the Red List assessment process itself has developed substantially over the past decade, extending the value of the Red List far beyond the assignation of threat status. We highlight here how the Red List, in conjunction with the comprehensive data compiled to support it and in spite of several important limitations, has become an increasingly powerful tool for conservation planning, management, monitoring and decision making.

Animals↗
PubMed2005

Wilderness and recreational neurology.

With increased access to once remote regions of the planet and renewed interest in exploring natural surroundings, previously geographically isolated and rare neurologic conditions can be encountered in any patient population. Rare envenomations and poisonings, once the purview of the tropical neurologist, now can be encountered by travelers to areas where creatures that have developed specialized defenses are endemic. Recognition, therefore, of the potentially neurotoxic fauna and flora in these areas holds value, even for the urban neurologist.

Animals↗
PubMed2004

Tyrphostin AGL-2043 eluting stent reduces neointima formation in porcine coronary arteries.

OBJECTIVE: Tyrphostin AGL-2043 is a potent tricyclic quinoxaline inhibitor of PDGF beta-receptor tyrosine kinase (PTK), Kit, and Flt3. We have shown previously that selective inhibition of PDGF beta-receptor PTK by tyrphostins markedly reduces SMC proliferation and migration in vitro, reduces neointima formation in balloon-injured porcine femoral arteries, and reduces neointimal stenosis in stented porcine coronary arteries when administered intramurally within biodegradable nanoparticles. The present study was designed to determine the effect of AGL-2043 delivered from a stent-based, biodegradable polymeric coating on neointima formation in the porcine coronary artery model. METHODS AND RESULTS: Stents coated with biodegradable, polylactic/glycolic acid (PLGA) polymer, with (n=13) or without (n=11) 180 mcg AGL-2043 were implanted into the proximal LAD of 24 Sinclair mini-pigs (34+/-4 kg) to achieve a 1.1:1 stent/artery diameter ratio. The delivery of drug from stent to tissue was confirmed by high-performance liquid chromatography. After 28 days, histomorphometric analysis showed that in-stent stenosis in animals treated with AGL-2043 was reduced by 50% (51+/-21% versus 26+/-10%, p=0.001), the absolute neointimal area was reduced by 44% (2.38+/-1.04 versus 1.31+/-0.43 mm(2), p=0.004), and the absolute luminal area was increased by 57% (2.19+/-1.09 versus 3.39+/-0.59 mm(2), p=0.003). There were no significant differences between control and AGL-2043 in injury score (1.24+/-0.11 vs. 1.15+/-0.12, p=0.07) or inflammation score (1.19+/-0.35 vs. 1.07+/-0.33, p=0.41). Moreover, the difference in % in-stent stenosis between control and treated animals remained highly significant even after normalizing the % stenosis to the degree of injury (p=0.0008) or to the inflammation score (p=0.001). Mortality for this study was zero. Tissue concentration in segments 1 cm proximal and distal to the stents, were negligible or zero at 1 h, 24 h, and 4 weeks after stent implantation. CONCLUSION: Stent-based delivery of tyrphostin AGL-2043 from a biodegradable polymeric coating reduces in-stent neointimal hyperplasia in porcine coronary arteries by 50% after 28 days and preserves lumen area. Long-term studies should be the next step in testing applicability to the human interventional setting.

Animals↗
PubMed2004

Early changes in experimental osteoarthritis using the Pond-Nuki dog model: technical procedure and initial results of in vivo MR imaging.

The purpose of this study was to prove the feasibility of combining in vivo MR imaging with the Pond-Nuki animal model for the evaluation of osteoarthritis. In an experimental study, 24 beagle dogs underwent transection of the anterior cruciate ligament of the left leg (modified Pond-Nuki model). The dogs were randomly assigned into four groups and examined by MRI after 6, 12, 24 and 48 weeks. MR imaging of both knees was performed under general anesthesia with the contralateral joint serving as control. In group 1 (6 weeks postoperatively), the first sign detected on MRI was subchondral bone marrow edema in the posteromedial tibia. After 12 weeks, erosion of the posteromedial tibial cartilage could be observed, followed by meniscus degeneration and osteophytosis after 24 and 48 weeks. The contralateral knee joint showed transient joint effusion, but no significant signs of internal derangement (P<0.001). By combining in vivo MR imaging with the Pond-Nuki model, it is possible to detect early signs of osteoarthritis. The first sign was posteromedial subchondral bone marrow edema in the tibia followed by progressive cartilage degeneration and joint derangement. The in vivo model therefore seems to be suitable for longitudinal studies or monitoring the therapeutic effects of osteoarthritis.

Animals↗
PubMed2004

Too much lumping in ischemic stroke - a new classification.

BACKGROUND: The heterogeneity of ischemic stroke syndromes with treatment of disparate categories may be a factor in clinical stroke trial failure. Recent advances include a multitude of stroke investigative modalities that are noninvasive, allowing more precise mechanistic determination. MATERIAL/METHODS: We retrospectively analyzed our young stroke patient population for stroke etiology according to the TOAST classification with five different etiological groups. Patients were assessed quantitatively according to the National Institute of Health Stroke Scale for neurological deficit and Rankin Scale for neurological handicap. Investigations included laboratory, Doppler sonograms of the cervicocephalic vessels, cardiac echocardiography and multimodality magnetic resonance imaging in all patients. Statistical analysis was performed, using a logit model for nominal response: log piJ/piJ)=alphaj+betajX. RESULTS: Amongst young stroke patients (n=133, women n=72) causes included other (n=77/119;65%), large vessel disease (LVD) (n=8/119;7%), small vessel disease (SVD) (n=17/119;14%), unknown (n=3/119;2%) and cardiac (n=14/119;12%). Within the other category at least 20 different etiologies were delineated. There were significant differences among the various categories (multinomial distribution with equal probabilities p=<0.0001). CONCLUSIONS: We recommend an expanded classification for stroke to include large vessel cerebrovascular disease, small vessel cerebrovascular disease, cardiogenic, dissection, prothrombotic states, migraine induced, cerebral venous thrombosis, vasculitides, vasculopathy other, miscellaneous and unknown.

Adolescent↗
PubMed2004

Effectiveness of the global protected area network in representing species diversity.

The Fifth World Parks Congress in Durban, South Africa, announced in September 2003 that the global network of protected areas now covers 11.5% of the planet's land surface. This surpasses the 10% target proposed a decade earlier, at the Caracas Congress, for 9 out of 14 major terrestrial biomes. Such uniform targets based on percentage of area have become deeply embedded into national and international conservation planning. Although politically expedient, the scientific basis and conservation value of these targets have been questioned. In practice, however, little is known of how to set appropriate targets, or of the extent to which the current global protected area network fulfils its goal of protecting biodiversity. Here, we combine five global data sets on the distribution of species and protected areas to provide the first global gap analysis assessing the effectiveness of protected areas in representing species diversity. We show that the global network is far from complete, and demonstrate the inadequacy of uniform--that is, 'one size fits all'--conservation targets.

Animals↗
PubMed2004

Rapid translation system: a novel cell-free way from gene to protein.

Proteome research has recently been stimulated by important technological advances in the field of recombinant protein expression. One major breakthrough was the development of a new generation of cell-free transcription/translation systems. The open and flexible character of these systems allows direct control over expression conditions via the addition of supplements to the expression reaction. The possibility of working with linear expression templates instead of cloned plasmids and the ease of downstream processing, circumventing the need for cell-lysis, makes them ideally suited for high-throughput screening applications. Among these novel cell-free systems, the Rapid Translation System (RTS) developed by Roche is the first one that is scalable from micrograms to milligrams of protein. This review describes the basic principles of RTS which differentiate it from traditional in vitro expression technologies, starting from template generation to high-end applications like labeling for structural biology research. Recent results obtained by RTS users from different institutions are presented to illustrate each step of a novel cell-free protein expression workflow and its benefits compared to traditional cell-based expression.

Cell Extracts↗
PubMed2004

Cognitive impairment in isolated subtentorial stroke.

BACKGROUND: Recent case reports have implicated subtentorial lesions of the brainstem or cerebellum as part of the neurocognitive circuitry. AIM: To determine whether cognitive impairment is part of the neurological deficit in isolated brainstem (IBSS) or cerebellar stroke (ICS), using bedside screening and formal neurocognitive assessment of higher cortical function. METHODS: Accrual occurred through a hospital based stroke registry. Cognitive bedside tests and neuropsychological tests were employed for the detection of higher cortical function. Scores from each test were converted to age and education based z-scores. Scores at or below -1.5 SD were clinically defined 'impaired'. Scores were averaged across tests in each functional area. RESULTS: Of the stroke patients (n = 1360), the infarct was isolated within the brainstem (IBSS) in (45 of 120 or 38%) and isolated within the cerebellum (ICI) in (37 of 79 or 46.8%). Comparison of the IBSS patients with cognitive impairment in one or more domains to those with brainstem (24 of 45 or 53%) and hemispheric cerebral infarcts: (43 of 72 or 58%) (Pearson Chi Square) was not significantly different (P = 0.49). The admission Canadian Neurological Score (mean 10.2, 95% CI: 9.7-10.2) and Rankin score at 1 month (mean 1.7, 95% CI: 2.1-1.4). Comparison of the number of ICI patients with cognitive impairment in one or more domains (13 of 37 or 35.1%) to those with cerebellar and hemispheric cerebral infarcts who had abnormal cognitive testing in one or more domains (16 of 36 or 44.4%) (Pearson Chi Square) was not significantly different (P = 0.41). The mean admission Canadian Neurological Scores for the ICI cases was 10.9 (95% CI: 10.5-11.2) on average. Their mean admission Rankin score was 1.7 (95% CI: 1.4-2.1). Neuropsychological testing for frontal/executive skills, immediate and delayed memory, and visuospatial abilities (n = 15), revealed that frontal abilities were most impacted by the isolated strokes in these patients (average frontal impairment index = -1.29 +/- 0.79) followed by delayed recall of verbal and visual information (mean = -1.18 +/- 1.17). Immediate memory (-0.51 +/- 0.75) and visuoconstructive skills (-0.06 +/- 0.88) were relatively spared. Overall, 47% of the patients showed impairment on frontal tasks while 40% had significant impairment in delayed recall. In contrast, only 13% had scores below the cutoff for immediate memory and none fell below the cutoff for visuoconstructive skills. CONCLUSION: Cognitive impairment is a common sequel of isolated subtentorial stroke. The frequency of impairment is similar either because of isolated brainstem or isolated cerebellar infarct, and similar to cognitive impairment with cerebral hemispheric lesions. Frontal networks or metacognition is the most frequently involved domain.

Adult↗
PubMed2003

Stentless aortic valves as an alternative to homografts for valve replacement in active infective endocarditis complicated by ring abscess.

BACKGROUND: The valve substitute of choice in active infective aortic valve endocarditis complicated by annulus abscess in our institution is the cryopreserved homograft. To avoid implantation of any prosthetic material, the Shelhigh No-React stentless valves and conduits may be considered an alternative when no suitable homograft is available. METHODS: Between March 1986 and January 2001, 452 homografts were implanted in the aortic position. From January 2000 to August 2001, 75 Shelhigh No-React prostheses were implanted at our institution. In 25 consecutive patients (study group) with aortic annulus abscess, urgent aortic valve replacement with the Shelhigh SuperStentless and Stentless Aortic Valve Conduit was undertaken. Patients (16 male, 9 female; age, 49 +/- 19 years) were studied with follow-up until March 2002. The control group comprised 68 consecutive historical patients (46 male, 22 female; age, 53 +/- 14.4 years) with similar disease treated between January 1997 and December 1999 in whom an aortic homograft was implanted. This group was also followed up until March 2002. Demographic data and preoperative characteristics of the patients were without significant differences. Patients were studied by echocardiography. RESULTS: Sixty-day mortality was 16% (11 patients) in the control group compared with 12% (3 patients) in the study group. Recurrent infection occurred in 4% in both groups. The instantaneous and mean Doppler gradients yielded no significant differences (19.4 +/- 10.4 mm Hg and 11.8 +/- 5.7 mm Hg versus 18.2 +/- 8.7 mm Hg and 10.9 +/- 5.3 mm Hg, respectively). The mean effective orifice area calculated from Doppler flow velocity for the stentless valve was 2.3 +/- 0.6 cm2. Preoperative evaluation of left ventricular dimensions and global left ventricular systolic function did not vary significantly between the two groups. However, postoperatively evaluated left ventricular end-diastolic diameter dimensions in the study group were significantly smaller than those in the control group (47.6 +/- 7.9 mm versus 56 +/- 9.5 mm; p = 0.05). Ejection fraction was similar in both groups (56.2% +/- 12.8% for the study [Shelhigh] and 52.6% +/- 16.8% for the control [homograft] group). CONCLUSIONS: Our experience with both the Shelhigh No-React SuperStentless and Stentless Aortic Valve Conduit in patients with native or prosthetic aortic valve endocarditis appears to demonstrate good results, similar to those of cryopreserved homografts. Ease of implantation and favorable effective orifice area and pressure gradients, as well as the No-React anticalcification treatment, are promising factors.

Abscess↗
PubMed2003

Sit4 phosphatase is functionally linked to the ubiquitin-proteasome system.

Using a synthetic lethality screen we found that the Sit4 phosphatase is functionally linked to the ubiquitin-proteasome system. Yeast cells harboring sit4 mutations and an impaired proteasome (due to pre1-1 pre4-1 mutations) exhibited defective growth on minimal medium. Nearly identical synthetic effects were found when sit4 mutations were combined with defects of the Rad6/Ubc2- and Cdc34/Ubc3-dependent ubiquitination pathways. Under synthetic lethal conditions, sit4 pre or sit4 ubc mutants formed strongly enlarged unbudded cells with a DNA content of 1N, indicating a defect in the maintenance of cell integrity during starvation-induced G(1) arrest. Sit4-related synthetic effects could be cured by high osmotic pressure or by the addition of certain amino acids to the growth medium. These results suggest a concerted function of the Sit4 phosphatase and the ubiquitin-proteasome system in osmoregulation and in the sensing of nutrients. Further analysis showed that Sit4 is not a target of proteasome-dependent protein degradation. We could also show that Sit4 does not contribute to regulation of proteasome activity. These data suggest that both Sit4 phosphatase and the proteasome act on a common target protein.

Amino Acid Sequence↗