Predictors of hippocampal atrophy in critically ill patients.

BACKGROUND AND PURPOSE: Hippocampal atrophy is presumably one morphological sign of critical illness encephalopathy; however, predictors have not yet been determined. METHODS: The data for this report derived from patients treated at the intensive care units (ICUs) of the University Hospital in Bonn in the years 2004-2006. These patients underwent structural magnetic resonance imaging 6-24 months after discharge. Volumes (intracranial, whole brain, white matter, grey matter, cerebral spinal fluid, bilateral hippocampus) were compared with healthy controls. Pro-inflammatory parameters and ICU scoring systems were explored in conjunction with brain volumes. Cut-scores were defined to differentiate patients with high from those with low inflammatory response. RESULTS: Hippocampal and white matter volume were reduced in critically ill patients compared with healthy controls. Procalcitonin showed a very strong correlation (r = -0.903, P = 0.01) and interleukin-6 a moderate correlation (r = -0.538, P = 0.031) with hippocampal volume, but not with other brain volumes. C-reactive protein was linked to grey matter volume. There was no correlation with systemic inflammatory response syndrome criteria (body temperature, heart rate, respiratory rate, white blood cell count) or for hippocampal or whole brain volume. Furthermore, parameters representing severity of disease (APACHE II score, SOFA score, duration of stay and duration of mechanical ventilation) were not associated with hippocampal or other brain volumes. CONCLUSIONS: This analysis suggests that high levels of procalcitonin and interleukin-6 in the blood serum of critically ill patients are associated with a high likelihood of hippocampal atrophy irrespective of the severity of disease measured by ICU scoring systems and other inflammatory parameters.

Association of transcobalamin c. 776C>G with overall survival in patients with primary central nervous system lymphoma.

BACKGROUND: Chemotherapy for primary central nervous system lymphoma (PCNSL) is based on methotrexate (MTX), which interferes with both nucleic acid synthesis and methionine metabolism. We have reported previously that genetic variants with influence on methionine metabolism are associated with MTX side effects, that is, the occurrence of white matter lesions as a sign of MTX neurotoxicity. Here, we investigated whether such variants are associated with MTX efficacy in terms of overall survival in MTX-treated PCNSL patients. METHODS: We analysed seven genetic variants influencing methionine metabolism in 68 PCNSL patients treated with systemic and facultative intraventricular MTX-based polychemotherapy (Bonn protocol). RESULTS: Median age at diagnosis was 59 years (range: 28-77), 32 patients were female. Younger age (Wald=8.9; P=0.003) and the wild-type C (CC) allele of the genotype transcobalamin c (Tc2). 776C>G (Wald=6.7; P=0.010) were associated with longer overall survival in a multivariate COX regression analysis. CONCLUSION: This observation suggests that the missense variant Tc2. 776C>G influences both neurotoxicity and efficacy of MTX in the Bonn PCNSL protocol.

The variant methylenetetrahydrofolate reductase c.1298A>C (p.E429A) is associated with multiple sclerosis in a German case-control study.

Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disease of the central nervous system. We investigated the association of two missense variants of the MTHFR gene, i.e. MTHFR c.677C>T (p.A222V) and c.1298A>C (p.E429A), in 138 patients with clinically definite multiple sclerosis of relapsing-remitting course and 138 age- and gender-matched healthy controls. No significant differences were found in the frequency of the MTHFR c.677C>T polymorphism between MS patients and healthy controls. However, the genotype frequencies of the missense variant MTHFR c.1298A>C were significantly different between patients (AA/AC/CC: 0.34/0.55/0.11) and controls (0.52/0.36/0.12; Pearson's chi(2)=11.1; p=0.004). These results suggest that homozygosity for the A allele of MTHFR c.1298A>C may be protective against the incidence of MS. If confirmed in an independent study sample, the underlying mechanisms should be investigated, which may lead to novel insights in biochemical factors influencing the aetiology and pathophysiology of MS.

Methotrexate-induced myelopathy responsive to substitution of multiple folate metabolites.

Methotrexate (MTX)-associated myelopathy is a rare but serious subacute complication of MTX-based chemotherapy. We report the case of a woman with breast cancer and meningeal carcinomatosis who developed severe progressive myelopathy after four cycles of intrathecal MTX administration. We substituted high doses of the key metabolites of the methyl-transfer pathway: S-adenosylmethionine (SAM), 200 mg three times daily i.v.; folinate, 20 mg four times daily i.v.; cyanocobalamin, 100 microg once daily i.v.; and methionine, 5 g daily p.o. The patient's paraparesis improved rapidly thereafter, and magnetic resonance (MR) imaging showed resolution of the intramedullary lesions. Genetic analyses revealed homozygosity for the A allele of methylenetetrahydrofolate reductase (MTHFR) c.1298A>C (p.E429A), whereas other genetic variants of folate/methionine metabolism associated with MTX neurotoxicity were not present. Substitution with multiple folate metabolites may be a promising strategy for the treatment of MTX-induced neurotoxicity.

Acute methotrexate-induced encephalopathy--causal relation to homozygous allelic state for MTR c.2756A>G (D919G)?

Methotrexate (MTX) is widely used in the treatment of hematological diseases. The typical side-effects of high-dose MTX chemotherapy on the CNS range from asymptomatic white matter changes to severe CNS demyelination. MTX neuro - toxicity has been described to be associated with homocysteine and folate levels as well as genetic variants affecting methionine metabolism. Here we describe a case of severe, acute MTX-induced encephalopathy in a patient who was found to be homozygous for the rare missense variant methionine synthase (MTR) c.2756A>G (D919G), which may have modified the effect of MTX on homocysteine metabolism. This finding encourages further studies to determine to what extent the individual conditions of folate and methionine metabolism influence the effects or side-effects of MTX treatment.

Human heart beta-adrenoceptors: beta1-adrenoceptor diversification through 'affinity states' and polymorphism.

1. In atrium and ventricle from failing and non-failing human hearts, activation of beta(1)- or beta(2)-adrenoceptors causes increases in contractile force, hastening of relaxation, protein kinase A-catalysed phosphorylation of proteins implicated in the hastening of relaxation, phospholamban, troponin I and C-protein, consistent with coupling of both beta(1)- and beta(2)-adrenoceptors to stimulatory G(salpha)-protein but not inhibitory G(ialpha)-protein. 2. Two 'affinity states', namely beta(1H) and beta(1L), of the beta(1)-adrenoceptor exist. In human heart, noradrenaline elicits powerful increases in contractile force and hastening of relaxation. These effects are blocked with high affinity by beta-adenoceptor antagonists, including propranolol, (-)-pindolol, (-)-CGP 12177 and carvedilol. Some beta-blockers, typified by (-)-pindolol and (-)-CGP 12177, not only block the receptor, but also activate it, albeit at much higher concentrations (approximately 2 log units) than those required to antagonize the effects of catecholamines. In human heart, both (-)-CGP 12177 and (-)-pindolol increase contractile force and hasten relaxation. However, the involvement of the beta(1)-adrenoceptor was not immediately obvious because (-)-pindolol- and (-)-CGP 12177-evoked responses were relatively resistant to blockade by (-)-propranolol. Abrogation of cardiostimulant effects of (-)-CGP 12177 in beta(1)-/beta(2)-adrenoceptor double-knockout mice, but not beta(2)-adrenoceptor-knockout mice, revealed an obligatory role of the beta(1)-adrenoceptor. On the basis of these results, two 'affinity states' have been designated, the beta(1H)- and beta(1L)-adrenoceptor, where the beta(1H)-adrenoceptor is activated by noradrenaline and blocked with high affinity by beta-blockers and the beta(1L)-adrenoceptor is activated by drugs such as (-)-CGP 12177 and (-)-pindolol and blocked with low affinity by beta-blockers such as (-)-propranolol. The beta(1H)- and beta(1L)-adrenoceptor states are consistent with high- and low-affinity binding sites for (-)-[(3)H]-CGP 12177 radioligand binding found in cardiac muscle and recombinant beta(1)-adrenoceptors. 3. There are two common polymorphic locations of the beta(1)-adrenoceptor, at amino acids 49 (Ser/Gly) and 389 (Arg/Gly). Their existence has raised several questions, including their role in determining the effectiveness of heart failure treatment with beta-blockers. We have investigated the effect of long-term maximally tolerated carvedilol administration (> 1 year) on left ventricular ejection fraction (LVEF) in patients with non-ischaemic cardiomyopathy (mean left ventricular ejection fraction 23 +/- 7%; n = 135 patients). The administration of carvedilol improved LVEF to 37 +/- 13% (P < 0.005); however, the improvement was variable, with 32% of patients showing pound 5% improvement. Upon segregation of patients into Arg389Gly-beta(1)-adrenoceptors, it was found that carvedilol caused a greater increase in left ventricular ejection faction in patients carrying the Arg389 allele with Arg389Arg > Arg389Gly > Gly389Gly.

Methionine metabolism and phenotypic variability in X-linked adrenoleukodystrophy.

A combined genotype of polymorphisms of methionine metabolism has been associated with CNS demyelination in methotrexate-treated patients. Within a sample of 86 patients with X-linked adrenoleukodystrophy, this genotype was overrepresented in a subgroup of 15 patients with adrenomyeloneuropathy (AMN) with CNS demyelination (adrenoleukomyeloneuropathy) in comparison to 49 AMN patients without CNS demyelination ("pure" AMN; p = 0.002), suggesting that methionine metabolism might contribute to the phenotypic variability in adrenoleukodystrophy.

Information processing in severe disorders of consciousness: vegetative state and minimally conscious state.

OBJECTIVE: To study the presence of electrophysiological indicators of remaining cortical functions in patients with persistent vegetative state (PVS) and minimally conscious state (MCS). Previous electrophysiological and PET data indicated that some PVS patients have partially intact cortical processing functions. However, it remains unclear whether the reported patients were representative for PVS population or just some exceptional cases. METHODS: Event-related brain responses to stimuli of different complexity levels, recorded in 98 patients with extremely severe diffuse brain injuries, 50 of which in PVS. Four main indicators of cortical functions were: (i) N1-P2 complex as an index of simple, undifferentiated cortical processing; (ii) mismatch negativity as an index of pre-attentive, probably unconscious, cortical orientation; (iii) P3 wave as an index of deep cortical analysis of physical stimuli, and (iv) brain responses to semantic stimuli. RESULTS: Cortical responses were found in all PVS patients with a background EEG activity > 4 Hz. All responses investigated, including those to semantic stimuli that indicated comprehension of meaning, occurred significantly above chance, though less frequently than in patients with severe brain injuries who were conscious. CONCLUSIONS: Cortical responses were lacking in most patients with severe EEG slowing (< 4 Hz). Follow-up data revealed that the presence of a mismatch negativity, a short disease duration, and the traumatic etiology were related to a better outcome. SIGNIFICANCE: The data show that in a subpopulation of PVS patients with preserved thalamocortical feedback connections, remaining cortical information processing is a consistent finding and may even involve semantic levels of processing.

A re-examination of twitching motility in Pseudomonas aeruginosa.

Twitching motility is a form of solid surface translocation which occurs in a wide range of bacteria and which is dependent on the presence of functional type IV fimbriae or pili. A detailed examination of twitching motility in Pseudomonas aeruginosa under optimal conditions in vitro was carried out. Under these conditions (at the smooth surface formed between semi-solid growth media and plastic or glass surfaces) twitching motility is extremely rapid, leading to an overall radial rate of colony expansion of 0.6 mm h(-1) or greater. The zones of colony expansion due to twitching motility are very thin and are best visualized by staining. These zones exhibit concentric rings in which there is a high density of microcolonies, which may reflect periods of expansion and consolidation/cell division. Video microscopic analysis showed that twitching motility involves the initial formation of large projections or rafts of aggregated cells which move away from the colony edge. Behind the rafts, individual cells move rapidly up and down trails which thin and branch out, ultimately forming a fine lattice-like network of cells. The bacteria in the lattice network then appear to settle and divide to fill out the colonized space. Our observations redefine twitching motility as a rapid, highly organized mechanism of bacterial translocation by which P. aeruginosa can disperse itself over large areas to colonize new territories. It is also now clear, both morphologically and genetically, that twitching motility and social gliding motility, such as occurs in Myxococcus xanthus, are essentially the same process.

Surface Properties of Alkylpyridinium Chlorides and the Applicability of the Pendant Drop Technique.

Measurement of interfacial tension isotherms and critical micelle concentrations (CMCs) of surfactant solutions is of major concern in surface science. In this study we investigate the group of cationic alkylpyridinium surfactants. Despite widespread applications, their physicochemical properties (especially tetra- and octadecylpyridinium chloride) are not so well characterized. The surface tension isotherms of 12 different surfactant/water/KCl systems are systematically determined by means of a new laser tensiometer (LASDA) with the pendant drop technique. The surfactants are purified using the Lunkenheimer method, which is capable of providing surfactants of high purity. From surface tension isotherms, values for excess concentrations, cross-sectional areas, and CMCs are obtained. The long-chain surfactants, especially octadecylpyridinium chloride, show some strange behavior, which is probably due to slow transport processes. We discuss in some detail diffusion limitations of the pendant drop technique that can drastically increase the time until equilibrium surface tension is reached, especially in the case of highly surface-active substances. Copyright 1999 Academic Press.

[A case report of malignant hyperthermia in a 14-month-old boy]. / Kasuistik einer malignen Hyperthermie bei einem 14 Monate alten Knaben.

A 14-month-old boy underwent bilateral antrotomies and adenotomy for bilateral mastoiditis. During the operation, typical symptoms of malignant hyperthermia (MH) became apparent. At the time of operation, pulse oximetry and capnometry were not possible which led to a delay in making the diagnosis. Nevertheless, Dantrolene, which was available in the operating theatre, was immediately administered. The postoperative recovery was complicated by altered cerebral function (inability to concentrate), muscle exhaustion and a coagulopathy which lasted for eleven days. A muscle biopsy of the child's father was positive for MH.