Dystonia in corticobasal degeneration.

OBJECTIVE: To characterize the clinical features, particularly dystonia, in patients with clinically diagnosed or pathologically proven corticobasal degeneration (CBD). BACKGROUND: Although dystonia has been reported in many neurodegenerative disorders, it has not been studied in CBD. Dystonia, often accompanied by painful rigidity and fixed contractures, is one of the most disabling features of CBD. METHODS: The medical records, imaging studies, and videotapes of 66 patients who satisfied the clinical criteria of CBD, evaluated between 1988 and 1998, were reviewed. The occurrence, nature, and distribution of dystonic features were analyzed and correlated with other features of CBD. RESULTS: Of the 66 patients with CBD, 39 (59.0%) had dystonia. The mean age at onset of initial symptoms was 63.9 years (range 44--75). In 20 (51.0%) patients, dystonic symptoms began in one arm, while 13 (33.0%) patients had initial leg involvement. At least one arm was affected in 36 (92.0%) dystonic patients. Although 11 (28.0%) patients had leg dystonia, the leg was the predominant site of involvement in only 1 patient. Only 12 (31.0%) patients had dystonia involving the head, neck, or trunk in the course of the disease. The diagnosis of CBD was confirmed in all 4 patients who had autopsies. CONCLUSION: In this large series of CBD patients we found that asymmetric limb dystonia, particularly affecting one arm, is a common manifestation of CBD; dystonia may be the initial manifestation of this neurodegenerative disorder. Axial or leg dystonia, without significant involvement of an arm, is rare. There is no effective treatment for this relentless disorder, except for temporary relief of dystonia and pain, with local botulinum toxin injections.

Dystonia in corticobasal degeneration.

Although a referral bias may have resulted in a higher proportion of atypical cases and consequently an overestimation of dystonia, asymmetric limb dystonia particularly affecting one arm initially was observed in 92% of all our CBD cases. Predominant leg dystonia is uncommon, and head, neck, or axial dystonia is rare. Dystonia is often associated with myoclonus, rigidity, apraxia, alien hand phenomenon, and sensory cortical signs in the affected limb, and there are no significant differences between the occurrence of these or other features, between patients with or without dystonia. There is no effective treatment for this relentless disorder except for temporary relief of dystonia and pain with local botulinum toxin injections. Further clinicopathologic studies are needed to elucidate the anatomical and physiologic substrates of dystonia in this disorder.

The physiology and biosynthesis of secondary metabolites.

Recently, several excellent reviews appeared /9, 12, 15, 29/ summarizing new findings of the last years and describing the topic in the new interconnections. The signalling systems through which changes in environmental conditions affecting the growth of microorganism are sensed, transmitted and converted into mechanisms controlling the production of antibiotic can now be investigated with the techniques of molecular genetics. Evidence has been accumulated that demonstrated the key roles played by diffusible molecules in regulating cellular differentiation even among prokaryotic microorganisms. This is exemplified by A-factor and its analogues, which act as autoregulators for morphological differentiation and secondary metabolism in Streptomyces. In our article we have concentrated on the physiological changes, which can occur during the growth in natural environment or during cultivation under laboratory conditions. Recent evidence for the presence of molecular signalling systems in Streptomyces is reviewed, along with the inherent implications. The constitution of the metabolic type during the first hours of cultivation has been previously reviewed /36/.

Constitution of the metabolic type of streptomycetes during the first hours of cultivation.

Using the examples of biosynthesis of streptomycin, bialaphos, actinorhodin, oligoketides and autoregulators during the first hours of streptomycete cultivation, it is stressed that the external environment in cooperation with the internal metabolic abilities of the cell determines the metabolic type that would develop during the life cycle of the producing streptomycetes. If we accept that a certain metabolic type (from the point of view of the production of secondary metabolites) was determined already during the first hours of cultivation of the microorganisms, we must also admit that the availability of primary metabolites in the so-called production phase of growth (stationary phase, idiophase, etc.) is to a certain extent determined by the very early stages of strain development.

Instability of the production of avermectins, sporulation, and pigmentation in Streptomyces avermitilis.

Production of avermectins, sporulation ability, and colony pigmentation were followed in Streptomyces avermitilis C-18/6 cultures during serial transfer (for eight subcultures) in four different liquid media. These phenotypes were found to be unstable and independent of each other. A procedure was established whereby depressed avermectin production could be reversed but the degree of reversion was dependent on the history of the isolate, i.e., the type of medium used. The presence of isoleucine as the sole N source caused an immediate loss of avermectin production and this could not be reversed.

Nitrogen regulation of fatty acids and avermectins biosynthesis in Streptomyces avermitilis.

Fatty acid composition was analysed in the producer of avermectins, Streptomyces avermitilis C-18 grown in chemically defined medium with different nitrogen sources. Significant differences in nitrogen regulation of fatty acid biosynthesis were found in this strain in comparison with other streptomycetes studied so far. This finding could be explained at the level of regulation of branched-chain amino acid metabolism.

Screening for a new generation of anthelminthic compounds. In vitro selection of the nematode Caenorhabditis elegans for ivermectin resistance.

Development of resistance to ivermectin in vitro is reported for the first time. Two strains of Caenorhabditis elegans D5 and D6 able to grow on agar plates after treating with up to 3 mg ivermectin per L were selected. The parent strain N2 was extremely sensitive to ivermectin, its growth being inhibited by treatment with 0.1-0.2 mg IVM per L.

Immunomodulators isolated from microorganisms.

Microbial products are surveyed that have an immunoregulatory activity, both from the realm of low-molar-mass compounds and from the group of naturally occurring polymers. The data include in most cases the producer organism or source, a brief chemical characteristic and biological activity. Various groups of substances are compared, the drawbacks attendant on their acquisition and application are pointed out and their advantageous properties are specified.

Vitamins as effectors of monensin production by Streptomyces cinnamonensis.

Vitamins added to submerged Streptomyces cinnamonensis cultures stimulated the production of monensins. Vitamins B2, B3, B5 and B12 enhanced the production by about 50%, vitamins B1 and B6 by 100%. The addition of biotin in optimal concentration resulted in more than 3-fold increase in total production.

Overproduction of microbial products--facts and ideas.

Overproduction of microbial metabolites is related to developmental phases of microorganisms. Inducers, effectors, inhibitors and various signal molecules play a role in different types of overproduction. Primary and secondary metabolism are interconnected. Biosynthesis of enzymes catalyzing metabolic reactions in microbial cells is controlled by well-known positive and negative mechanisms, e.g. induction, repression, catabolite repression, mechanisms controlling enzyme activity include isosteric and allosteric interactions, e.g. competitive and non-competitive inhibition, allosteric effects, molecular conversion etc. Biosynthesis of secondary metabolites is catalyzed by unaltered enzymes of primary metabolism, by altered enzymes of primary metabolism and by specific enzymes of secondary metabolism. In addition to classical mutagenesis and selection of suitable microbial cells, methods of molecular genetics are used in the overproduction of microbial products.

The effect of inorganic phosphate on the production of avermectin in Streptomyces avermitilis.

The effect of phosphate on the production of avermectin B1a, growth and utilization of glucose in the course of cultivation of Streptomyces avermitilis on a complex and chemically defined medium has been studied. Phosphate added at the beginning of cultivation at 1-20 mmol/l did not distinctly affect the production of secondary metabolite. From the results it follows that the biosynthesis of avermectin tolerates high concentrations of phosphate in the medium.

Propionate and the production of monensins in Streptomyces cinnamonensis.

Variants resistant to propionate were prepared from a mutant strain of Streptomyces cinnamonensis producing predominantly monensin A. Using selected resistants the production of monensins (in media with higher concentrations of propionate) was examined. Stimulation of monensin synthesis by propionate was observed with 70% of the resistants studied. Propionate did not influence the ratio between monensin A and B production.

Production of quinomycin A in Streptomyces lasaliensis.

In addition to lasalocid, an oligoether coccidiostatic compound, other compounds are synthesized by Streptomyces lasaliensis. Mutants producing either of two antibiotics, lasalocid A or quinomycin A (an antibiotic of quinoxaline character), were obtained by natural selection and by mutagenesis. Methods of isolation, purification and estimation of both compounds were established.

Biosynthesis of monensins A and B: the role of isoleucine.

Isoleucine added to the cultivation medium of Streptomyces cinnamonensis C-100-5 induced a relative increase of the production of monensin B at the expense of monensin A. U-14C-Isoleucine was found not to be a specific monensin B precursor. The incorporation of 1-13C-2-methylbutyrate into monensins A and B showed the label to be evenly incorporated in both products at carbon atoms originating from C(1) of propionate. In regulatory mutants insensitive to 2-amino-3-chlorobutyrate isoleucine influenced the production of monensins only slightly but strains resistant to 2-aminobutyrate and norleucine decreased their total production by 2-12% in the presence of isoleucine which was associated with a decrease of monensin A content by 14-52%. The inhibitory effect of isoleucine on the biosynthesis of valine, a specific precursor of the butyrate unit of monensin A, is discussed.

Synthesis and biological activity of (7S)-O-epoxyalkyl derivatives of daunomycinone.

Synthesis and antibacterial activity of a number of 7-O-epoxyalkyl derivatives of daunomycinone prepared from 7-O-alkenyl derivatives of daunomycinone are described along with their inhibitory effect on leukemia P 388 cells.

Effect of precursors on biosynthesis of monensins A and B.

Precursors of monensins (acetate, propionate, butyrate, isobutyrate) affect the total production and the relative proportion of monensins A and B. Addition of propionate into the fermentation medium causes a prevalence of monensin B whereas butyrate and isobutyrate stimulate the production of monensin A and suppress the production of monensin B.