Hermann Am Mucke

Data From the VITA Study Do Not Support the Concept of Vascular Depression

OBJECTIVE Cerebrovascular lesions that are apparent in magnetic resonance scans and regioselective atrophy of the brain have been proposed as a causative or exacerbating factor in depression with late-life onset. The objective of this study was to investigate whether deep white matter or periventricular hyperintensities, small ischemic lesions, and brain atrophy contribute to late-onset depression in the nondemented elderly. METHOD Based on a group of 606 individuals of identical age (75.8 years, standard deviation: 0.45 years) residing in two districts of Vienna, the authors built a case-control cohort (ratio: 1:4) consisting of 51 individuals with late-onset major or minor depression matched with 204 subjects of identical gender and education status without depression, resulting in two groups that were homogenous with respect to age, place of residence, gender, and education. Scores for focal brain lesions, mediotemporal lobe atrophy, and ventricular enlargement as well as risk factors for vascular disease were compared with cognition and depression status. RESULTS Depressed individuals had significantly lower scores than nondepressed subjects in all measures of cognitive and executive function. No significant relation was found between a diagnosis of depression and any type of discrete brain lesions, but measures of brain atrophy (Cella Media indices, mediotemporal atrophy) showed a clear statistical relation to depression. No relationship was found between depression and lipid parameters. CONCLUSION The authors found no indication that white matter hyperintensities or minor ischemic lesions played a role in our depressed cohort, casting doubt on the vascular hypothesis of late-onset depression.

Partial characterization of the genome of the ‘endosymbiotic’ cyanelles from cyanophora paradoxa

Cyanophoru paradoxa, a flagellate of uncertain taxonomic position, is capable of growing photoautotrophically and its cyanelles are generally accepted to be endosymbiotic blue-green algae [ 11. In electron micrographs these ‘endosymbionts’ are characterized by a rudimentary cell wall which differentiates them clearly from any known type of chloroplast [2]. Furthermore the cyanelles have been shown to be sensitive to lysozyme [3] and to contain N-acetyl muramic acid and 2,6-diaminopimelic acid in their envelopes [4]. Unlike those from other host organisms the cyanelles from C’anophora paradoxa to date cannot be cultivated in vitro. It thus appears that these cyanelles represent semiautonomous organelles which could be envisaged as being intermediates between free living blue-green algae and chloroplasts [5]. The use of reassociation kinetics [6] to determine a genome size of 117 megadaltons for the DNA of these cyanelles seems to underline the above. This value is comparable to genome sizes of -90-l 30 megadaltons observed for ctDNAs of green algae and higher plants [7]. However the kinetic complexities from freeliving Cyanophyceae are in the range of 1.6-3 X lo9 daltons [8] and hence 1 order of magnitude larger. Here the isolation and purification of the cyanelle DNA and the results of its cleavage by restriction endonucleases are reported. We find a size 115 + 5 megadaltons and the results show in addition that the

Cyanelle DNA from Cyanophora paradoxa

SummaryCyanelles which have been found in few eukaryotic organisms are photosynthetically active organelles which strikingly resemble cyanobacteria. The complexity of the cyanelle genome in Cyanophora paradoxa (127 Kbp) is too low to consider them as independent organisms in a symbiotic relationship. In order to correlate cyanelle genome and gene structure with those of plastid chromosomes of other plants, a circular map of the cyanelle DNA from Cyanophora paradoxa (strain LB555 UTEX) has been constructed using the restriction endonucleases SalI (generating 6 DNA fragments), BamHI (6), SalI (5), XhoI (9), and BglII (19).Besides the rRNA genes (16S, 23S, 5S), genes for 14 proteins have been located on this circular map. Among those are components of several multienzyme complexes involved in photosynthetic electron transport, as well as the large subunit of ribulose-1,5-bisphosphate carboxylase and two ribosomal proteins. All the probes used, were derived from a collection of spinach chloroplast DNA clones. Hybridization experiments showed signals to DNA fragments primarily from the large single-copy region of cyanelle DNA. The arrangement of genes on cyanelle DNA is different from that on spinach chloroplast DNA. However, genes which have been shown to be cotranscribed in spinach chloroplasts are also clustered on cyanelle DNA.

The central part of the cyanelle rDNA unit of Cyanophora paradoxa: Sequence comparison with chloroplasts and cyanobacteria

The 287-bp spacer and the flanking 3′-end of the 16S- and 5′-end of the 23S-rRNA genes of the cyanelles from Cyanophora paradoxa have been sequenced and compared with the corresponding regions of cyanobacteria and chloroplasts. The spacer contains the uninterrupted genes for tRNAile and tRNAala. All coding regions show high homology to their prokaryotic counterparts. At the 3′-end of the 16S-rDNA a CCTCCTTT sequence has been identified which is complementary to putative ribosome binding sites observed immediately upstream of the coding region of cyanelle protein genes.

No evidence for cognitive improvement from oral nicotinamide adenine dinucleotide (NADH) in dementia

Summary. Reduced nicotinamide adenine dinucleotide (NADH) is advertised as an over-the-counter product or dietary supplement to treat Alzheimers disease. We performed a 3-month open-label study with oral 10 mg/day NADH with 25 patients with mild to moderate dementia of the Alzheimer, vascular, and fronto-temporal types in addition to their current cholinomimetic drug medication. In 19 patients who completed the study, we found no evidence for any cognitive effect as defined by established psy-chometric tests. We conclude that NADH is unlikely to achieve cognitive improvements in an extent reported earlier, and present theoretical arguments against an effectiveness of this compound in dementia disorders.

Cognitive relapse after discontinuation of drug therapy in Alzheimer's disease: cholinesterase inhibitors versus nootropics

Summary. In a cross-sectional study of outpatients diagnosed with dementia of the Alzheimer type who had been treated with a broad variety of drugs supposed to improve cognition or to delay cognitive decline, we have investigated the effects of abruptly discontinuing therapy on cognition. Termination of therapy with any cholinesterase inhibitor was associated with a cognitive decline during the following 6–7 weeks which was significantly more pronounced than that experienced by patients who had received nootropic drugs or calcium channel blockers (3.41 vs. 1.17 points on the ADAS-Cog scale; −1.14 vs. −0.06 points on the MMSE scale). This effect was not modified by gender, apolipoprotein E genotype, or the extent of ventricular enlargement on CT scans. Its magnitude was comparable to the cognitive response observed in published clinical trials when cholinesterase therapy commenced, and also with the data obtained during a 6-week placebo washout phase.

Iguratimod: a new disease-modifying antirheumatic drug.

Iguratimod, a methanesulfonanilide, is a novel disease-modifying antirheumatic drug that has been developed exclusively in Japan and China. It inhibits the production of immunoglobulins and various inflammatory cytokines (interleukin-1, -6 and -8 and TNF), and exerts anabolic effects on bone metabolism by stimulating osteoblastic differentiation and inhibiting osteoclastogenesis. On the molecular level, it inhibits the nuclear transcription factor NF-κB but not its inhibitor, IκBα. In addition to these immunomodulatory and other long-lasting effects, iguratimod inhibits cyclooxygenase-2, which provides a synergistic short-term action against pain and inflammation. Efficacy and tolerability are comparable to salazosulfapyridine, and probably also to methotrexate. Combination with methotrexate is synergistic in patients with insufficient response to methotrexate and does not significantly increase adverse events. Liver enzyme elevations and thrombocytopenia are the most significant side effects to watch for. In summary, iguratimod is a welcome addition to the small-molecule drug therapy of rheumatoid arthritis.

Comparison of the cyanelle DNA from two different strains of Cyanophora paradoxa.

SummaryThe cyanelle DNA from two different strains of Cyanophora paradoxa (strain LB555UTEX and strain 1555) was investigated.The cyanelle DNA from both strains showed a buoyant density in neutral CsCI gradients of 1.692 g/cm3. The total molecular weight, as judged by restriction endonuclease analysis, of the two cyanelle DNAs differed. In strain LB555UTEX the size of the cyanelle DNA was equivalent to 127 ± 1 kb whereas in strain 1555 a size of 138 ± 1 kb was consistently found. The sizes of individual DNA fragments and the number of recognition sites for a particular restriction endonuclease appeared largely unrelated.A high amount of cross hybridization, as judged by reciprocal heterologous DNA hybridizations, however indicated a high degree of sequence homology between the two cyanelle DNAs. Under comparable conditions, cyanelle DNA hybridized nearly exclusively with the dG+dC-rich rRNA transcription units from plastid DNAs. Up to now conserved restriction endonuclease recognition sites between the two cyanelle DNAs were only observed within the cyanelle rRNA genes which are present twice on both cyanelle DNAs.

The role of imatinib in the treatment of pulmonary hypertension.

Imatinib mesylate, a receptor tyrosine kinase inhibitor that has been approved for several oncology conditions, is currently under investigation for pulmonary arterial hypertension. The therapeutic rationale is that its targets, platelet-derived growth factor receptor beta (PDGFR-β) and proto-oncogene c-Kit, are pivotal for the proliferation, migration and apoptosis resistance of peripheral artery smooth muscle cells which reduces the lumen of the pulmonary artery, leading to diminished blood oxygenation and pressure overload in the right heart ventricle. Interfering with this process could slow disease progression, which is incompletely addressed by current therapies which focus on vasorelaxation. Results from two efficacy studies have been reported; while the first missed its primary endpoint (but provided valuable insights on efficacy in subgroups), the phase III IMPRES study and its ongoing extension revealed an impressive degree of added benefit for imatinib against a background of conventional combination therapy. The side effect profile of imatinib in this condition requires more investigation.

Zotepine for behavioural and psychological symptoms in dementia: an open-label study.

OBJECTIVE To provide initial information on the safety and efficacy of the atypical antipsychotic zotepine in the treatment of behavioural and psychological symptoms of dementia (BPSD). METHODS This was an open-label, single-centre field study. Twenty-four patients with BPSD associated with Alzheimers disease (n=12) or other forms of dementia (n=12) were included. During the 8-week observation period, the patients received zotepine (Nipolept) [12.5-150 mg/day] for the psychotic components of BPSD; no other treatment interventions for BPSD were allowed. At baseline, day 28 and day 56, patients were evaluated using the Clinical Global Impressions (CGI) scale; the Mini-Mental State Examination (MMSE), the Syndrome Brief Test (SKT) and the Age Concentration Test (AKT) to assess cognition; and the Neuropsychiatric Inventory (NPI) and the Cohen-Mansfield Agitation Inventory (CMAI) to assess BPSD. General adverse effects and, more specifically, the emergence of extrapyramidal symptoms were also assessed. RESULTS There was no change from baseline to day 56 in the CGI score and the caregiver burden (as indicated by the caregiver-related section of the NPI). There was also no change in cognition (as assessed by the MMSE, SKT and AKT). The neuropsychiatric symptom score according to part 1 of the NPI (especially key psychotic symptoms, aggression and disinhibition) and the CMAI scores improved by 36% and 15%, respectively, between baseline and the end of the study in a highly statistically significant fashion. No significant differences in treatment response or adverse effect profile were noted between the 12 patients with Alzheimers disease and the 12 patients with other types of dementia. Zotepine was well tolerated, with tiredness and sedation (five and four cases, respectively) being the most frequent complaints. No clinically significant emergence of extrapyramidal symptoms was seen. CONCLUSIONS Zotepine appears to be well tolerated and effective in treating BPSD, consistent with the performance of other atypical antipsychotic drugs in this condition. Larger, controlled studies are warranted.