Prediction of general practice workload from census based social deprivation scores.

The aim was to compare the ability of census based social deprivation scores devised by Jarman, Carstairs, and Townsend to predict workload in general practice. This was a prospective study of 140,050 patients registered with general practices over one year from 1 July 1981 (Third National Morbidity Survey). Main outcome measures were workload score for each patient, defined as a weighted sum of consultations at the surgery and consultations elsewhere, excluding preventive procedures. 25 general practices in England and Wales. In multivariate analyses the Jarman, Carstairs, and Townsend indices all predicted workload, but the Townsend index was the best predictor, with both housing tenure and car ownership being strong predictors of workload. The overcrowding and geographical mobility variables used in the Jarman index did not predict increased workload. The weighting assigned to children under five by the Jarman index underestimated the additional workload this group generated. For identifying social pressures on general practice workload the Jarman index is less valid than other census based scores because it fails to include car ownership and housing tenure. A more rational scheme for compensating general practitioners would directly weight the capitation fee for children aged under five years and allocate current deprivation payments according to the Townsend index or a similar score. This would redistribute resources from London to deprived areas in northern England.


Is questionnaire information valid in the study of a chronic disease such as diabetes? The Nord-Trøndelag diabetes study.

The aim was to validate information about diabetes mellitus collected by questionnaire in a large epidemiological survey. Questions on diabetes diagnosis, medical treatment for diabetes, diabetes duration, and hypertension treatment were selected from the Nord-Trøndelag health survey questionnaires. One of the municipalities was selected for the validation study. The health survey 1984-86 addressed all inhabitants > or = 20 years of age in Nord-Trøndelag county, Norway; 76,885 (90.3%) of the eligible population participated in answering the question on diabetes. All inhabitants in the municipality answering "yes" to the question on diabetes (n = 169) and the persons with the same sex born closest before and after each diabetic patient and answering "no" to the diabetes question (n = 338) were included. A very thorough search was made in the medical files of the general practitioners in the municipality for corresponding information. Compared to the files, diabetes was verified in 163 out of the 169. The commonest cause of discrepancy was renal glycosuria. One out of the 338 registered non-diabetic persons was found to have diabetes. Diabetic patients tended to overestimate diabetes duration significantly. Insulin treatment was verified in 19/20 (95%) and treatment with oral hypoglycaemic agents in all 44 with an affirmative questionnaire answer. A negative answer on insulin and oral hypoglycaemic agents was verified in 100% and 99% respectively. The concordance was considerably higher than in a comparable Norwegian study performed 10 years earlier. Patient administered questionnaires may be a very reliable source of information for epidemiological purposes in a well defined chronic disease such as diabetes mellitus.


Individual morbidity and neighbourhood deprivation in a non-metropolitan area.

The aim was to replicate, in a non-metropolitan area, a study by Curtis based on data from different parts of London which found a significant relationship between individual morbidity and neighbourhood deprivation. This study used the same design as the previous study. Information on individual morbidity was obtained, using the Nottingham health profile. Deprivation scores were assigned to respondents according the Jarman (and also Townsend) scores of the enumeration district in which they lived. Logistic regression models were built, using the enumeration district as the unit of analysis, to see if, after allowance for age and sex, the Jarman (or Townsend) score significantly improved the prediction of the enumeration district being above or below the sample median to any of the six dimensions of the profile. The survey involved households in 10 electoral wards in Colchester and Clacton, Essex, United Kingdom, in 1988. A systematic sample of 200 persons was drawn from the electoral register in each of 10 wards yielding 2000 names. Nottingham health profiles were obtained from 1555 respondents out of an initial sample of 2000 names from the electoral register; the response rate among those alive and resident at a valid address was 93%. Jarman and Townsend scores were assigned to 1496 of the respondents, and the 162 enumeration districts were used as a unit of analysis. Contrary to Curtis's finding, Jarman score did not add significantly in a multiple logistic regression model to the prediction of response to any of the six dimensions of the Nottingham health profile, nor did the Townsend score. Apart from chance variation, there are two possible explanations for this finding. The measures of deprivation may be valid in London but not elsewhere; or there may be a true difference between cities and towns in the effect that deprivation has on subjective health.


The ascending laparoscope. Modern thoracoscopy.

Developments in laparoscopic endoscopy have increased the interest in thoracoscopy. New techniques and instruments, particularly video endoscopy, have greatly expanded the indications for laparoscopic procedures. These innovations and techniques are being applied and modified for thoracic application.


Pregnancy and epilepsy.

Problems facing women who have epilepsy and are considering pregnancy are reviewed. Despite enormous medical and social advances, they remain at risk for various complications to themselves and to their offspring. Risk to the baby from maternal seizure and exposure to anticonvulsant drugs is considered. The clinician should chart a middle ground, minimizing fetal exposure to anti-convulsants while controlling maternal seizures.


The dieffenbachia plant. Case history.

When ingested, the common house plant dieffenbachia can lead to significant toxicity and possibly death if timely medical attention is not forthcoming following initial exposure. The deleterious effects should not be overlooked especially when children are involved who, naturally curious, may bite into this innocuous looking plant. Although the patient in this case was a type II diabetic on insulin, neither hypo- nor hyperglycemia developed. There was no other significant electrolyte imbalance despite the acute stressor placed on him.


GTPases.

GTPases represent a large family of proteins involved in a wide variety of cellular processes. They function as switches in which they are "on" in the GTP bound state and "off" in the GDP bound state. The "on" and "off" states are regulated by proteins which interact with the GTPases and enhance their rate of either GTP hydrolysis or GDP-GTP exchange. Thus far, GTPases have been shown to be involved in protein synthesis, signal transduction, control of cell growth, and intracellular transport.


Two mechanisms for growth inhibition by elevated transport of sugar phosphates in Escherichia coli.

The Escherichia coli uhp T gene encodes an active transport system for sugar phosphates. When the uhp T gene was carried on a multicopy plasmid, amplified levels of transport activity occurred, and growth of these strains was inhibited upon the addition of various sugar phosphates. Two different mechanisms for this growth inhibition were distinguished. Exposure to glucose-6-phosphate, fructose-6-phosphate or mannose-6-phosphate, which enter directly into the glycolytic pathway, resulted in cessation of growth and substantial loss of viability. Cell killing was correlated with the production of the toxic metabolite, methylglyoxal. In contrast, addition of 2-deoxyglucose-6-phosphate, galactose-6-phosphate, glucosamine-6-phosphate or arabinose-5-phosphate, which do not directly enter the glycolytic pathway, resulted in growth inhibition without engendering methylglyoxal production or cell death. Inhibition of growth could result from excessive accumulation of organophosphates in the cell or depletion of inorganic phosphate pools as a result of the sugar-P/Pi exchange process catalysed by UhpT. The phosphate-dependent uptake of glycerol-3-phosphate by the GlpT antiporter was strongly inhibited under conditions of elevated sugar-phosphate transport. There are thus two separate toxic effects of elevated sugar-phosphate transport, one of which was lethal and related to increased flux through glycolysis. It is likely that the control of uhpT transcription by catabolite repression exists to limit the level of UhpT transport activity and thereby prevent the toxic events that result from elevated uptake of its substrates.


Pyruvate catabolism during transient state conditions in chemostat cultures of Enterococcus faecalis NCTC 775: importance of internal pyruvate concentrations and NADH/NAD+ ratios.

NADH/NAD+ ratios and internal pyruvate concentrations were determined during switches between aerobic and anaerobic steady-state conditions of glucose-limited chemostat cultures of Enterococcus faecalis. During the switch experiments, changes in catabolic fluxes were observed: transition from anaerobic to aerobic conditions resulted in a complete and instantaneous conversion of glucose into acetate and CO2 via the pyruvate dehydrogenase complex, while during a switch from aerobic to anaerobic conditions the culture became homolactic. A similar switch to a homolactic fermentation was observed upon release of the limitation by addition of a glucose pulse to the culture. In sharp contrast to this, a pyruvate pulse resulted in an increase of both pyruvate formate-lyase and pyruvate dehydrogenase complex activity. Furthermore, acetoin was formed during a pyruvate pulse, probably due to a dramatic increase in internal pyruvate concentration. Regulation of the catabolic fluxes over the various pyruvate-catabolizing enzymes is discussed in view of the observed changes in internal pyruvate concentrations and NADH/NAD+ ratios.


Physiological analysis of mutants of Saccharomyces cerevisiae impaired in sulphate assimilation.

The assimilation of sulphate in Saccharomyces cerevisiae, comprising the reduction of sulphate to sulphide and the incorporation of the sulphur atom into a four-carbon chain, requires the integrity of 13 different genes. To date, the functions of nine of these genes are still not clearly established. A set of strains, each bearing a mutation in one MET gene, was studied. Phenotypic studies and enzyme determinations showed that the products of at least five genes are needed for the synthesis of an enzymically active sulphite reductase. These genes are MET1, MET5, MET8, MET10 and MET20. Wild-type strains of S. cerevisiae can use organic metabolites such as homocysteine, cysteine, methionine and S-adenosylmethionine as sulphur sources. They are also able to use inorganic sulphur sources such as sulphate, sulphite, sulphide or thiosulphate. Here we show that both of the two sulphur atoms of thiosulphate are used by S. cerevisiae. Thiosulphate is cleaved into sulphite and sulphide prior to utilization by the sulphate assimilation pathway, as the metabolism of one sulphur atom from thiosulphate requires the presence of an active sulphite reductase.


The catabolism of branched-chain amino acids occurs via 2-oxoacid dehydrogenase in Saccharomyces cerevisiae.

Saccharomyces cerevisiae possesses 2-oxoacid dehydrogenase (EC 1.2.4.4) similar to that found in mammalian cells. The activity is readily detected in cells which have been cultured in a minimal medium containing a branched-chain amino acid. Mutants defective in lipoamide dehydrogenase also lack 2-oxoacid dehydrogenase and are thus unable to catabolize branched-chain amino acids: 2-oxoacids accumulate in the cultures of these cells. The 2-oxoacid dehydrogenase activity is distinct from both 2-oxoglutarate dehydrogenase and pyruvate dehydrogenase, because it could not be detected in assay conditions which permitted the measurement of 2-oxoglutarate dehydrogenase and vice versa. In addition, a strain lacking 2-oxoglutarate dehydrogenase (kgd1::URA3) retained 2-oxoacid dehydrogenase as did a mutant specifically lacking pyruvate dehydrogenase (pda1::Tn5ble). In complex media the specific activity of this enzyme is highest in YEP (yeast extract-peptone)-glycerol and lowest in YEP-acetate and YEP-fructose. 2-Oxoacid dehydrogenase could not be detected in cells which had been transferred to sporulation medium. These results suggest that in S. cerevisiae the catabolism of branched-chain amino acids occurs via 2-oxoacid dehydrogenase, not via the 'Ehrlich Pathway'.


Cloning and characterization of genes induced by hydrogen peroxide in Bacillus subtilis.

Transcriptional fusions of Bacillus subtilis DNA to the lacZ gene were screened for induction, initially by ethanol and then by hydrogen peroxide (H2O2). Two fusions were identified which were induced late following treatment with sublethal concentrations of H2O2 (100 microM). The oxy-1 promoter was induced 4-5-fold and mapped to 11 degrees while the oxy-2 promoter was induced 20-fold and mapped close to the right of the defective prophage PBSX, at about 120 degrees. The oxy-2 fusion was induced by mitomycin C as well as H2O2, which correlated with the induction of PBSX by these agents. This was probably not a transcriptional induction, but rather a consequence of the induction of PBSX replication extending into adjacent regions of the chromosome.


Bacillus subtilis SenS exerts its activity through a site in the 5' flanking region of the aprE promoter.

The Bacillus subtilis gene senS, when present in high copy number, stimulates the expression of several extracellular protein genes during the onset of stationary phase, e.g. aprE. A novel integration vector, pINT, was constructed for transcription expression studies; it employed a unique method of promoter insert production for fusion with the lacZ reporter gene. Deletions were made of the 5' flanking region of the aprE promoter to localize the site responsible for SenS-mediated enhancement activity. pINT was used translationally fuse aprE promoter deletion fragments with the lacZ reporter gene. A site between -177 and -415 with respect to the aprE start site of transcription was found to be required for the maximal SenS-mediated transcription increase from the aprE promoter. A multicopy vector containing the senS coding region without its native negative regulation was highly unstable in B. subtilis; this was due to the expressed senS insert.


Isolation and characterization of Escherichia coli mutants affected in aerobic respiration: the cloning and nucleotide sequence of ubiG. Identification of an S-adenosylmethionine-binding motif in protein, RNA, and small-molecule methyltransferases.

We report the isolation and characterization of a mutant of Escherichia coli unable to grow aerobically on non-fermentable substrates, except for very slow growth on glycerol. The mutant contains cytochrome oxidases o and d, and grows anaerobically with alternative electron acceptors. Oxygen consumption rates of cell-free extracts were low relative to activities in an isogenic control strain, but were restored in vitro by adding ubiquinone-1 to cell-free extracts. Transformation with a cloned 2.8 kb ClaI-EcoRV fragment of chromosomal DNA restored the ability of this mutant (AN2571) to grow on succinate and also restored cellular quinone levels in this strain. The plasmid also complemented a previously isolated ubiG mutant (AN151) for aerobic growth on succinate. The nucleotide sequence revealed a 0.7 kb portion of gyrA. Unidirectional nested deletions from this fragment and complementation analysis identified an open reading frame encoding a protein with a predicted molecular mass of 26.5 kDa. This gene (ubiG) encodes the enzyme 2-octaprenyl-3-methyl-5-hydroxy-6-methoxy-1,4-benzoquinone methyltransferase, which catalyses the terminal step in the biosynthesis of ubiquinone. The open reading frame is preceded by a putative Shine-Dalgarno sequence and followed by three palindromic unit sequences. Comparison of the inferred amino acid sequence of UbiG with the sequence of other S-adenosylmethionine (AdoMet)-dependent methyltransferases reveals a highly conserved AdoMet-binding region. The cloned 2.8 kb fragment also contains a sequence encoding the C-terminus of a protein with 42-44% identity to fungal acetyl-CoA synthetases.


Global transcription pattern of phi C31 after induction of a Streptomyces coelicolor lysogen at different growth stages.

Using two complementary strategies for low-resolution S1 mapping, the global pattern of phi C31 transcription was studied after induction of thermoinducible phi C31 lysogens of Streptomyces coelicolor A3(2). A complex pattern of early transcripts was seen, with a peak of abundance at about 10 min post-induction. Nearly all of these transcripts were from DNA located to the right of the c (repressor) gene and to the left of the attP site: a region of about 14 kb. Early transcription was also observed immediately to the left of the c gene. The c gene itself was also induced, with an earlier expression peak (about 5 min post-induction). Primary late transcripts were generally relatively long, but degraded. They apparently corresponded to most of the 18 kb region to the left of the c gene. Some shorter and more persistent late transcripts corresponded to DNA close to or overlapping the cos site. Large late transcripts from a region close to the left-hand end of the phi C31 genome showed evidence of processing to more stable, smaller RNA species. A failure of older cultures (more than 12 h old) to be induced productively was correlated with a much longer period of early transcription, reduced late transcription, failure to synthesize a major virion protein, and failure to package phi C31 DNA. Moreover, heat treatment of the older lysogenic cultures did not result in the phi C31-dependent shut-down of host rRNA transcription previously observed for young cultures (Rodríguez et al., Journal of General Microbiology (1986) 132, 1695-1701; Clayton & Bibb, Molecular Microbiology (1990) 4, 2179-2185).


Analysis of the flagellin (hag) gene of alkalophilic Bacillus sp. C-125.

Motility of the alkalophilic Bacillus sp. C-125, a flagellate bacterium, was demonstrated to be Na(+)- and pH-dependent. Flagellin protein from this strain was purified to homogeneity and the N-terminal sequence determined. Using the hag gene of Bacillus subtilis as a probe, the hag gene of Bacillus sp. C-125 was identified and cloned into Escherichia coli. Sequencing of this hag gene revealed that it encodes a protein of 272 amino acids (M(r) 29,995). The predicted N terminal sequence of this protein was identical to that determined by N-terminal sequencing of the flagellin protein from strain C-125. The alkalophilic Bacillus sp. C-125 flagellin shares homology with other known flagellins in both the N- and C-terminal regions. The middle portion, however, shows considerable differences, even from that of flagellin from the related species, B. subtilis.


Identification of hydrophobic proteins FepD and FepG of the Escherichia coli ferrienterobactin permease.

In Escherichia coli, iron assimilation by means of the siderophore enterobactin requires two hydrophobic cytoplasmic membrane proteins, FepD and FepG, which are essential components of a binding-protein-dependent transport system. Such components are typically difficult to detect. Here we report observation of the fepD and fepG gene products in polyacrylamide gels; they appeared as diffuse bands at positions consistent with smaller sizes than those predicted by sequence analysis. Translational coupling was suggested by the lack of a detectable product from the fepG message in the absence of translation of the upstream fepD message. The orientation of FepD/FepG in the membrane was predicted based on their similarities in sequence and hydrophobicity to FhuB.


Site-directed mutagenesis of the hydrogenase signal peptide consensus box prevents export of a beta-lactamase fusion protein.

A secretion vector, pVN1, expressing the [NiFe] hydrogenase signal peptide of Desulfovibrio vulgaris Hildenborough fused to beta-lactamase from Escherichia coli was constructed in order to study the unusual characteristics of hydrogenase signal peptides, which share a strictly conserved sequence, the consensus box: R-R-X-F-X-K. Although the hydrogenase signal peptide-beta-lactamase fusion protein was processed much more slowly than the fusion of beta-lactamase with its own signal peptide, the system mimicked several features expected for hydrogenase biosynthesis in E. coli, including increased export under anaerobic conditions. Site-directed mutagenesis of R(-28), the first arginine residue of the consensus box, to a glutamate completely inhibited export and processing of the fusion protein. The same mutation of R(-33), located outside the consensus box, had almost no effect. The data indicate a specific role for the consensus box sequence in the export mechanism for hydrogenase.


Preparation of right-side-out plasma membrane vesicles from Penicillium cyclopium: a critical assessment of markers.

A plasma membrane fraction was obtained by the combined use of differential centrifugation and aqueous polymer two-phase partitioning techniques. Vanadate-inhibited ATPase and glucan synthase activities were highly enriched in this fraction, although the presence of ATPase activity which was not inhibited by vanadate, nitrate, molybdate, anyimycin A or azide was also detected. Other intracellular membrane marker activities were present at very low or undetectable levels. A further separation step using Percoll density gradient centrifugation resulted in the separation of a fraction which exclusively contained vanadate-inhibited ATPase activity, and was enriched with silicotungstic-acid-staining membrane material. Latency tests performed on the plasma membrane markers showed that the membrane vesicles were in the right-side-out orientation.


Characterization of an anaerobic fungus from llama faeces.

An anaerobic fungus was isolated from llama faeces. Based on its morphological characteristics, polyflagellated zoospores, extensive rhizoid system and the formation of monocentric colonies, the fungus is assigned to the genus Neocallimastix. Neocallimastix sp. L2 is able to grow on several poly-, oligo- and monosaccharides. It differs from other Neocallimastix isolates in its inability to ferment inulin. Neocallimastix sp. L2 requires CO2 for growth. In the presence of 100% CO2 in the gas phase glucose is fermented to H2, CO2, formate, acetate, lactate, succinate and ethanol (33.8, 15.4, 74.3, 69.2, 26.7, 8.2, and 28.7 mmol per 100 mmol glucose, respectively). Reduced sulphur compounds can be used as sulphur source and ammonium or amino acids as nitrogen source. The temperature range for glucose fermentation is from 37 to 42 degrees C with an optimum of around 38 degrees C. The pH range for glucose fermentation is from pH 6 to pH 8 with a broad optimum between pH 6.5 and pH 7.5. The zoospores of Neocallimastix sp. L2 contain ribosomal 'globules' and hydrogenosomes. In the kinetosomes of the zoospores spurs, scoops and skirts are visible. In both the rhizoids and the sporangia 'crystal bodies' and hydrogenosomes are present. Mitochondria were not detected in either of these life stages.


Estimation of chromosome number and size by pulsed-field gel electrophoresis (PFGE) in medically important Candida species.

The chromosomal DNAs of eight medically important Candida species, C. albicans, C. stellatoidea, C. tropicalis, C. parapsilosis, C. krusei, C. guilliermondii, C. kefyr and C. glabrata, were analysed by pulsed-field gel electrophoresis under various conditions. The corresponding bands in the gels were assigned by three kinds of DNA probe which hybridized to DNA of all the species: rDNA, TUB2 and PEP4. The best conditions for separating the chromosomal DNAs were investigated and the numbers and molecular sizes of the chromosome bands were determined for each species. The chromosomal DNAs of the species were separated into 5-14 bands ranging in size from 0.5 to 4.5 Mb. Based on the quantification of the chromosome band intensities using a laser fluorescent gel scanner, the chromosome numbers were estimated. The apparent average total number of chromosomes per cell was 16 for C. albicans, 16 for C. stellatoidea, 12 for C. tropicalis, 14 for C. parapsilosis, 8 for C. krusei, 8 for C. guilliermondii, 18 for C.kefyr, and 14 for C. glabrata; the total chromosomal DNA size of each species per cell was calculated at about 31 Mb, 33 Mb, 31 Mb, 26 Mb, 20 Mb, 12 Mb, 29 Mb and 14 Mb, respectively.


Campylobacter helveticus sp. nov., a new thermophilic species from domestic animals: characterization, and cloning of a species-specific DNA probe.

An atypical group of thermophilic catalase-negative Campylobacter strains, the 'CH' (Swiss) group, can be recovered from faeces of domestic cats and dogs after selection by filtration, or with the antibiotic cefoperazone. This group of strains shows no relative DNA homology with any species in rRNA superfamily VI (Vandamme et al., 1991, International Journal of Systematic Bacteriology 41, 88-103) except with four thermophilic Campylobacter species, notably C. upsaliensis. The group is homogeneous and possesses a DNA base composition, cellular morphology at the electron microscope level and phenotypic properties characteristic of Campylobacter. Nonetheless it is distinct from known species of Campylobacter in terms of conventional bacteriological tests, total cellular protein profile, rRNA gene profile, and genomic DNA homology. On the basis of an integrated study of phenotype and genotype, we conclude that these bacteria constitute a previously undescribed species for which we propose the name Campylobacter helveticus sp. nov. A species-specific recombinant DNA probe was cloned from the designated type strain (NCTC 12470) for use in identification and further analysis of the epidemiology, pathogenicity and transmission of C. helveticus.


Monoclonal antibodies to Gliocladium roseum, a potential biological control fungus of sap-staining fungi in wood.

Immunological probes were developed to discriminate between a potential biological control fungus and sap-staining fungi present in wood. This paper describes the production of monoclonal antibodies to isolated cell wall fragments of the biological control fungus Gliocladium roseum. Two monoclonals, designated 6A5 and 3F12, were characterized. Their specificity was assessed by ELISA, by immunogold silver staining light microscopy, by immunogold electron microscopy, and by immunoblotting. Monoclonal 6A5 specifically recognized G. roseum and closely related species and did not react with any of 21 sap-staining fungi tested. Monoclonal 3F12 recognized most of the biological control fungi tested and also showed reactivity with two of the 21 sap-staining fungi. Both monoclonals appeared to recognize carbohydrate epitopes of the cell wall in G. roseum. Although the antibodies were produced against the cell wall of fungus grown in liquid culture, they also detected specific fungi in wood and, therefore, can be used for studies of wood colonization by fungi and for investigations of the interactions between different fungi growing on wood.


Toxicity of oxalysine and oxalysine-containing peptides against Candida albicans: regulation of peptide transport by amino acids.

A lysine antimetabolite, L-4-oxalysine [H2NCH2CH2OCH2CH(NH2)COOH], and oxalysine-containing di-, tri-, tetra- and pentapeptides inhibited growth of Candida albicans H317. Micromolar amounts of amino acids were found to overcome ammonium repression of the di- and tripeptide transport system(s) in strain H317. Several amino acids increased the toxicity of oxalysine-containing di- and tripeptides for C. albicans with little or no increase in toxicity of oxalysine or oxalysine-containing tetra- and pentapeptides. L-Lysine completely reversed the toxicity of oxalysine by competing with the transport of oxalysine into the cells. In contrast, L-lysine increased the toxicity of oxalysine-containing di- and tripeptides, but had no effect on the toxicity of oxalysine-containing tetra- and pentapeptides. Incubation of cells with L-lysine for 4 h resulted in a 15-fold increase in the rate of transport of radiolabelled dileucine, indicating that increased sensitivity of C. albicans to some toxic peptides in the presence of L-lysine may be attributed to an increased rate of transport of these peptides. Our results indicate that the dipeptide and tripeptide transport system(s) of C. albicans are regulated by micromolar amounts of amino acids in a similar fashion to the regulation of peptide transport in Saccharomyces cerevisiae and that multiple peptide transport systems differentially regulated by various nitrogen sources and amino acids exist in C. albicans.


Physiology and morphology of Legionella pneumophila in continuous culture at low oxygen concentration.

Two strains of Legionella pneumophila serogroup 1 monoclonal subgroup Pontiac were grown for the first time in continuous culture using a chemically defined medium. The influence of temperature on physiology and morphology was investigated by fixing the growth rate (equal to the dilution rate, D) at 0.08 h-1 and controlling the pH and dissolved oxygen concentration of the culture. Serine provided the principal source of carbon and energy but growth was limited by tyrosine. The bacterium behaved as a microaerophile in this medium, with maximal growth occurring at 0.31 (mg O2)I-1 (equivalent to a dissolved oxygen tension of 4% (v/v) air saturation at 30 degrees C). The cultures consisted of flagellated, short rods at 24 degrees C, but exhibited an increased level of pleomorphism and the loss of flagella as the temperature was increased to 37 degrees C. The presence of intracellular granules was noted, and their abundance was temperature-dependent. Polyhydroxybutyrate was present in L. pneumophila, and the proportion of the cell dry weight that it accounted for varied with temperature, being maximal at 24 degrees C. The ratio of saturated to unsaturated fatty acids in the cells decreased as the temperature was reduced towards 24 degrees C, so as to maintain membrane fluidity at low growth temperature.


The primary structures of helices A to G of three new bacteriorhodopsin-like retinal proteins.

The primary structures of helices A to G of all bacteriorhodopsin (BR)-like retinal proteins identified in newly isolated halobacteria have been determined from the nucleotide sequence of the BR-like protein genes. Using PCR methods, gene fragments encoding the A- to G-helix region of BR-like proteins were directly amplified from the total genomic DNA of the seven new halobacterial strains. Oligonucleotide primers corresponding to highly conserved regions in the helices A to G were designed from the nucleotide sequences of bacterioopsin (bop) and archaeopsin-I (aop-I), and some primers were effective for the amplification of the gene encoding C- to G-helix region of all new BR-like proteins. The primer corresponding to A-helix region was designed either from the nucleotide sequence of bop and aop-I or from the N-terminus amino acid sequence of a BR-like protein. Three new BR-like proteins were identified from the amino acid sequence, which was deduced from the nucleotide sequence of the genes encoding A- to G-helix region of the BR-like proteins. It was found that not only the amino acid sequence, but also the nucleotide sequence of the gene encoding the C- and G-helix region, in which a number of important residues for proton translocation are located, is highly conserved in three new BR-like proteins. Analysis of the primary structures of the A- to G-helix region of new BR-like proteins revealed that one has about 85% homology with aR-I and aR-II, and the rest have about 55% homology with halobium BR, aR-I and aR-II.(ABSTRACT TRUNCATED AT 250 WORDS)


A novel polysaccharide hydrolase cDNA (celD) from Neocallimastix patriciarum encoding three multi-functional catalytic domains with high endoglucanase, cellobiohydrolase and xylanase activities.

A plant polysaccharide hydrolase cDNA, designated celD, was isolated from a cDNA library of the rumen fungus Neocallimastix patriciarum. The enzyme encoded by celD had endoglucanase, cellobiohydrolase and xylanase activities. Deletion analysis revealed that celD cDNA can be truncated to code for three catalytically active domains. Each domain had the same substrate specificity as the enzyme produced by the untruncated celD and also possessed cellulose-binding capacity. Substrate competition studies showed that carboxymethylcellulose and xylan appear to compete with methylumbelliferyl cellobioside for the same active site within each domain. Expression of celD transcript in the rumen fungus was constitutive and was not affected by the presence of cellulose in the culture medium.


Chromosomal targeting of replicating plasmids in the yeast Hansenula polymorpha.

Using an optimized transformation protocol we have studied the possible interactions between transforming plasmid DNA and the Hansenula polymorpha genome. Plasmids consisting only of a pBR322 replicon, an antibiotic resistance marker for Escherichia coli and the Saccharomyces cerevisiae LEU2 gene were shown to replicate autonomously in the yeast at an approximate copy number of 6 (copies per genome equivalent). This autonomous behaviour is probably due to an H. polymorpha replicon-like sequence present on the S. cerevisiae LEU2 gene fragment. Plasmids replicated as multimers consisting of monomers connected in a head-to-tail configuration. Two out of nine transformants analysed appeared to contain plasmid multimers in which one of the monomers contained a deletion. Plasmids containing internal or flanking regions of the genomic alcohol oxidase gene were shown to integrate by homologous single or double cross-over recombination. Both single- and multi-copy (two or three) tandem integrations were observed. Targeted integration occurred in 1-22% of the cases and was only observed with plasmids linearized within the genomic sequences, indicating that homologous linear ends are recombinogenic in H. polymorpha. In the cases in which no targeted integration occurred, double-strand breaks were efficiently repaired in a homology-independent way. Repair of double-strand breaks was precise in 50-68% of the cases. Linearization within homologous as well as nonhomologous plasmid regions stimulated transformation frequencies up to 15-fold.


PBS2, a yeast gene encoding a putative protein kinase, interacts with the RAS2 pathway and affects osmotic sensitivity of Saccharomyces cerevisiae.

The yeast gene PBS2 encodes a presumed protein kinase. The gene is essential for manifestation of resistance to the antibiotic polymyxin B. Deletion of PBS2 enables a ras2-530 null mutant to grow on nonfermentable carbon sources; overexpression of PBS2+ enhances viability of a RAS2Val19 mutant. Overexpression of PBS2+ also diminishes cellular response to mating pheromone MF alpha. These results suggest that the PBS2 and RAS2 genes affect a common pathway that may communicate with the pheromone response pathway. In addition, disruption of PBS2 renders cells sensitive to high osmolarity: exposure to 0.9 M-NaCl causes growth arrest, appearance of bizarre morphological forms, and eventual death. A mutation suppressing pbs2 deletion has been found. That mutation restores full polymyxin B resistance but only partially corrects the osmotic sensitivity defect. These observations indicate that PBS2 is involved in diverse physiological pathways in yeast.


Purification and characterization of a dual function 3-dehydroquinate dehydratase from Amycolatopsis methanolica.

Studies on hydroaromatic metabolism in the actinomycete Amycolatopsis methanolica revealed that the organism grows rapidly on quinate (but not on shikimate) as sole carbon- and energy source. Quinate is initially converted into the shikimate pathway intermediate 3-dehydroquinate by an inducible NAD(+)-dependent quinate/shikimate dehydrogenase. 3-Dehydroquinate dehydratase subsequently converts 3-dehydroquinate into 3-dehydroshikimate, which is used partly for the biosynthesis of aromatic amino acids, and is partly catabolized via protocatechuate and the beta-ketoadipate pathway. Enzyme studies and analysis of mutants clearly showed that the single 3-dehydroquinate dehydratase present in A. methanolica has a dual function, the first example of a 3-dehydroquinate dehydratase enzyme involved in both the catabolism of quinate and the biosynthesis of aromatic amino acids. This enzyme was purified over 1700-fold to homogeneity. Its further characterization indicated that it is a Type II 3-dehydroquinate dehydratase, a thermostable enzyme with a large oligomeric structure (native M(r) 135 x 10(3)) and a subunit M(r) of 12 x 10(3). Characterization of aromatic amino acid auxotrophic mutants of A. methanolica suggested that genes encoding 3-dehydroquinate synthase and 3-dehydroquinate dehydratase are genetically linked but their transcription results in the synthesis of two separate proteins.


Synthesis, structure, antimicrobial, and genotoxic activities of organotin compounds with 2,6-diacetylpyridine nicotinoyl- and isonicotinoylhydrazones.

A series of organotin compounds obtained from the reaction of 2,6-diacetylpyridine nicotinoyl- and isonicotinoylhydrazones with tri- and diorganotin chlorides was investigated. The IR and 119Sn NMR spectroscopic characterization of all the compounds is reported, together with the x-ray crystal structure of [SnEt2(H2dapin')]2[SnEt2Cl3]Cl3.2H2O (H2dapin' = 2,6-diacetylpyridine bis(isonicotinoylhydrazone)). The main feature in this compound is the presence of a tin atom in both the complex ionic units. The coordination polyhedron is a pentagonal bipyramid in the cation and a trigonal bipyramid in the anion. Results are discussed concerning the in vitro evaluation of antimicrobial properties and genotoxic potential of the compounds described. In all cases the complexes show a reduced antimicrobial activity as compared to that of the corresponding organotin compound. Genotoxic properties of the ligands, detected in the Ames test, disappear in the complexes.


Diuretic activity of organomercury (II) complexes of theophylline and theobromine.

Organomercury(II) complexes of the types, p-XC6H4HgL (A) and p-XC6H4HgCl(L') (B) [LH = theophylline; L' = theobromine; X = Me, NO2], have been synthesised and characterized. Conductance measurements indicate that the complexes are non-electrolytes. The structures of the complexes have been elucidated by spectral studies (IR, UV, and 1H, 13C NMR). The complexes have been tested for diuretic activity. The structure-activity relationship has been propounded.


Ultraviolet radiation and ultra-clean air enclosures in operating rooms. UV-protection, economy, and comfort.

Ultraviolet radiation (UVC), as an air-cleaning method for operating rooms, has received increasing attention, due to its low cost. Recent work shows that UVC can provide ultra-clean air (< 10 CFU/m3) in the operating room. However, the UVC air-cleaning method has been criticized because of the protective clothing needed and the risk of UVC exposure for staff and patients. To evaluate the practicability of the UVC method, the aspects of UV-protection were thoroughly evaluated regarding UVC intensities and the transmission properties of clothing commonly used in the operating room. A comparison between UVC and the Charnley-Howorth enclosure, regarding the aspects of economy and comfort, was performed.


Pulmonary embolism. Incidence in primary cemented and uncemented total hip arthroplasty using low-dose sodium warfarin prophylaxis.

During a 5 1/2-year period from January 1984 to July 1989, 736 patients between the ages of 50 and 75 with a diagnosis of osteoarthritis had either cemented or uncemented primary total hip arthroplasty. Patients were treated with low-dose sodium warfarin for prophylaxis against pulmonary embolism and had preoperative and postoperative serial lung scanning. The overall incidence of pulmonary embolism was not statistically different between the cemented and uncemented groups (3.87% and 6.19%, respectively; P > .05). Eighty-one percent of the pulmonary emboli were asymptomatic. The incidence of pulmonary embolism was higher in men than in women (7.3% and 2.93%, respectively; P < .05) but did not differ within each individual sex for the cemented and uncemented groups. Of greater significance, when the two initial groups were matched to control for sex and weight differences (564 patients), the incidence of pulmonary embolism narrowed to 4.3% and 5.3% in the cemented and uncemented groups, respectively (P > .55). These data indicate that the use of uncemented total hip arthroplasty does not offer any additional protective value against pulmonary embolism when using low-dose sodium warfarin prophylaxis.


Clinical and radiographic results of the Muller straight stem used as a press-fit.

Prior to the introduction of porous coating, 21 patients had 24 ME Muller straight-stem femoral prostheses inserted as a press fit for the treatment of osteoarthrosis. Five hips have been revised for aseptic loosening; the remaining 19 prostheses are still in situ after a mean of 7.3 years (range, 6.2-8.3 years). A prospective clinical assessment has been undertaken using a modified Harris hip score, with scores increasing on average from a preoperative 43 to a postoperative 79. Eighteen of the 19 remaining hips are functioning well. Variable distances of subsidence are evident in 10 hips. Despite the use of a prosthesis that was not designed for cementless proximal wedge fitting, the results indicate an exceptionally low incidence of bone resorption and lysis. Unlike cemented and some porous-coated prostheses, stress shielding and osteopenia were not a feature in this series.


Bone ingrowth into porous-coated tibial components implanted with autograft bone chips. Analysis of ten consecutively retrieved implants.

Ten asymmetric porous-coated tibial knee components were consecutively retrieved from nine patients with implantation times ranging from 1 week to 48 months. Morselized autograft bone chips were applied to the resected surface of the tibia prior to component implantation. Microradiographic analysis showed bone in contact with 64 +/- 10% of the porous-coated interface. Backscattered electron imaging of the bone-implant interface revealed bone within 8-22% of the porous coating. Although bone in the form of autograft bone chips was observed in the porous coating of the 1 and 3 week specimens, it was not connected to the host bone. By 3 and 6 months, the bone chips were integrated and connected to the host bone providing osseous continuity from the porous coating to the skeleton. This study shows that reproducible bone ingrowth into porous-coated tibial components is achievable using autograft bone chips to promote bone fixation.


Revision arthroplasty facilitated by ultrasonic tool cement removal. An evaluation of whole bone strength in a canine model.

Ultrasonic driven tools have been developed to facilitate the removal of bone cement during revision arthroplasty. The effect on whole bone strength of cement removal by ultrasonic tools was examined in a canine femur model. Paired, fresh-frozen canine femora were divided into two groups. In group A, one femur from each pair was subjected to cement extraction with ultrasonic tools. In group B, one femur from each pair was subjected to manual cement extraction. Contralateral femora from each pair served as controls to determine the strength of intact femora. Torsional fractures were produced using a servocontrolled hydraulic testing machine (Minneapolis Testing System, Minneapolis, MN). Maximum torque, maximum angle, and energy capacity to failure were determined. Results were recorded as a reduction in percent value of the tested specimen versus the contralateral control. When comparing femora with cement removal by ultrasonic tools to the contralateral control femur, there were no statistical differences in ultimate torque (P = .83), maximum angle (P = .89), and energy capacity (P = .74) by analysis of variance. In addition, there were no significant differences between the group with ultrasonic tool cement removal and the group with manual tool removal. The authors conclude that in this canine model, removal of cement with ultrasonically driven tools has no adverse effects on whole bone strength.


Unrecognized femoral fractures during cementless total hip arthroplasty in the dog and their effect on bone ingrowth.

Uncemented straight-stemmed proximally porous-coated femoral components were press fitted into the femoral canals of seven dogs using a rasp 0.5 mm smaller than the components (press-fit group). In seven other dogs the components were fit precisely into the femoral canals using a rasp that was the same size as the components (control group). Using this technique, all of the dogs in the press-fit group developed longitudinal fractures in the femoral cortex, while none of the dogs in the control group developed fractures. None of the fractures were recognized at operation. Two of the dogs in the press-fit group displaced the fractures at 1 week and were sacrificed. The other five dogs were bearing weight on their limbs and completed the 3-week experimental period. Follow-up radiographs of these femurs showed marked periosteal new bone formation, but did not reveal any fractures. Serial sections of these femurs showed longitudinal healing fractures in the anterior cortex. The fractures had an adverse effect on the bone ingrowth into the porous surface of the press-fit group compared to the control group without fractures, and the porous surface adjacent to the fractures was ingrown with fibrous tissue. The amount of bone ingrowth expressed as a percentage of the porous coating area measured, on average, only 3.9% in the press-fit group at 3 weeks compared to 5.6% in the control group--a statistically significant difference at P < .025. This experience in the dog illustrates the inherent risk of driving a larger femoral component into a smaller cavity prepared in the femur.(ABSTRACT TRUNCATED AT 250 WORDS)


Assessment of intrapelvic cement and screws in revision total hip arthroplasty.

Vascular injury resulting from primary and revision hip arthroplasty has been reported to involve both arterial and venous structures. While such complications are extremely uncommon, removal of intrapelvic cement or screws during revision surgery can be hazardous to intrapelvic structures. Both arterial and venous perforations can occur, depending on the level at which the pelvic wall has been breached, and on the orientation of the intruding matter. Complications can be minimized with careful preoperative assessment of pelvic anatomy. Contrast-enhanced computerized tomography scanning can assist the revision surgeon with preoperative planning in those patients requiring removal of intrapelvic components. This technique appears to be an accurate, simple, and noninvasive method by which these intrapelvic relationships may be examined.


A prospective study of 100 consecutive Harris-Galante porous total hip arthroplasties. 2-5-year results.

This is a prospective study of the authors' first 100 Harris-Galante porous total hip arthroplasties (THA) that were followed for 2-5 years. The mean age of the 83 patients was 43 years. Using the Harris hip rating system, 80% of the hips were rated as excellent, 13% as good, 5% as fair, and 2% as poor at final evaluation. Eighty percent of the hips had no pain, 11% had slight or occasional pain, 8% had activity-related pain, and 1% had moderate pain. Eighty-seven percent of the hips had no limp, 8% had a slight limp, and 5% had a moderate limp. One femoral component, placed as a conversion of a loose bipolar hemiarthroplasty, has been removed for loosening. Two other hips have been reoperated, one for lengthening the femoral neck and one for changing the acetabular liner. There were no problems with acetabular screw fixation and no component migrated. Only two hips had 1 mm nonprogressive radiolucent lines in all three zones. Femoral component subsidence of 3 or more mm was measured in 16 hips, but was progressive in only 1. Radiolucent and radiodense lines were frequently seen in the nonporous coated regions of the femoral stem. Loss of proximal medial femoral bone density was seen in 59% of hips, and calcar resorption was seen in 16% of hips. Although the clinical results of this uncemented implant system were good or excellent in 93% of hips, the high incidence of femoral component subsidence is worrisome.


The effect of preoperative knee deformity on the initial results of cruciate-retaining total knee arthroplasty.

Between November 1985 and June 1987, 751 posterior cruciate-sparing total knee arthroplasties were performed on 523 patients who exhibited fixed varus or valgus deformities. Patients excluded from this study included the following: those with a postoperative follow-up period of less than 2 years (including patients who had died), patients who became infected, and patients with previous failed total knee arthroplasty in the same knee. A total of 473 knees left for evaluation. All arthroplasties were measured using anatomic axis for alignment measurement. The Hospital for Special Surgery scoring system was used to determine the clinical scores prior to the end of each follow-up examination. All ligament releases were performed sequentially, including balancing of the posterior cruciate ligament. All arthroplasties were divided into six separate groups depending upon the degree of varus or valgus deformity. Kaplan-Meier curves were constructed using three methods of failure definition. Curves were then compared between groups. The mean Hospital for Special Surgery score was no different between any of the groups, except for the group of 6 degrees-10 degrees varus, which was significantly higher than the mean score of the 11 degrees and higher valgus group. All other groups were the same statistically. It is concluded that severe varus and valgus deformities may be satisfactorily corrected with the use of a cruciate-retaining type of total knee arthroplasty.


Implications of reference axes used for rotational alignment of the femoral component in primary and revision knee arthroplasty.

A careful review of the literature revealed that no data had been reported on the angular difference or similarity between the posterior condylar axis used by many surgeons for primary total knee arthroplasty and the transepicondylar axis, which has been considered a useful anatomical landmark for femoral component placement in revision total knee arthroplasty. The purpose of this study was to determine whether measurable differences exist between the posterior condylar axis and the transepicondylar axis of the human femur. Nineteen pairs of human donor femora were measured. This study demonstrated that when the posterior condylar axis was taken as 0 degrees of rotation, the transepicondylar axis was found to be approximately 5 degrees externally rotated for both right and left femora, a significant difference (P < .05). However, there was no statistically significant difference in the angle measured between the posterior condylar axis and the transepicondylar axis when comparisons were made between matched right and left femora (P > .05). It is suggested that this information can be applied to improving the techniques currently used in the placement of both primary and revision femoral knee components.


Acetabular micromotion as a measure of initial implant stability in primary hip arthroplasty. An in vitro comparison of different methods of initial acetabular component fixation.

Micromotion has been shown to affect bony ingrowth into cementless components. This study was designed both to quantitate initial micromotion at the prosthesis-periacetabular bony interface and to compare different methods of commonly employed acetabular component fixations, ie, a press-fit hemispherical titanium cup, a press-fit hemispherical titanium cup with one and two dome screws, a press-fit titanium hemispherical cup with three spikes, and a cemented chromium-cobalt cup. The press-fit component without screws demonstrated the greatest motion equaling 162 microns at the ilium, 97 microns at the publis, and 54 microns at the ischium. With one and two screws placed into the dome, the mean ileal displacement decreased by 28 microns (17%) and 36 microns (22%), respectively. Dome screw placement demonstrated a minimal effect at the pubis and ischium. Compared to the press-fit component without augmentation, the tri-spike motion was less at the pubis and ischium. The cemented prosthesis provided the least amount of motion in all three areas tested. This experiment demonstrates that the ilium provides the least amount of support to immediate acetabular fixation, while the pubis (anterior column) and ischium (posterior column) provide more stability. One dome screw does not affect the stability of a hemispherical prosthetic cup significantly. A two dome screw fixation provides an added method of support at the ilium, but fails to decrease motion at the pubis or ischium significantly. The tri-spike fixation does not restrict motion at the ilium to the extent as the dome screws, but its effect at the ischium and pubis is much more pronounced. The obvious difference between initial motion seen with cemented versus uncemented components may suggest that before surgery, patients may need a period of protected weight bearing until ingrowth has occurred.


Protein-tyrosine kinase inhibition: mechanism-based discovery of antitumor agents.

Protein-tyrosine kinases (PTKs) have been shown to induce the cascade of altered cell parameters characteristic of transformed cells. This proposition provides an important rationale for the discovery of potential antitumor agents from natural sources on the basis of inhibition of PTK activity. Numerous naturally occurring and synthetic analogues of PTK inhibitors were systematically evaluated in this review based on their structure-activity relationships and potential antitumor efficacy.


Antimutagenic agents from natural products.

Certain secondary metabolites found in terrestrial and marine plants and organisms have evinced the capability for inhibiting the mutagenicity toward Salmonella typhimurium of a number of mutagens. These include 2-aminoanthracene (2AN), ethylmethanesulfonate (EMS), and benzo-[a]pyrene(B[alpha]P). The sensitivity of the antimutagenicity assay is such that crude extracts can be evaluated and purification of extracts readily followed. Major classes of antimutagenic compounds that have been isolated include flavonoids, coumarins, and cymopols.


A colorimetric microassay for the detection of agents that interact with DNA.

A simple microtiter assay for the detection of compounds that bind DNA is described. Agents that displace methyl green from DNA are detected spectrophotometrically by a decrease in absorbance at 630 nm. The feasibility of using the assay for detecting DNA-active compounds in fermentation extracts was assessed, and the activities of reference compounds in the methyl green assay and an ethidium bromide displacement method were compared.


Scalarane-type bishomosester terpenes from the sponge Phyllospongia foliascens.

Five new 20,24-bishomoscalarane sesterterpenes, phyllactones A [1], B [2], C [3], D [4], and E [5], are reported from the sponge Phyllospongia foliascens collected in the waters of the Nansha Islands in the South China Sea. Structural elucidation of these compounds is based on spectral data and chemical conversions. Phyllactones A and B show moderate cytotoxicity against KB cells (IC50 20 micrograms/ml).


Studies on the synthesis of sesquiterpene lactones, 14. Syntheses of (-)-arbusclin D and (+)-4-EPI-arbusclin D: the stereochemical assignment of arbusclin D.

Efficient syntheses of (-)-arbusclin D and (+)-4-epi-arbusclin D are reported. By these syntheses the C-4 stereochemistry of arbusclin D and the absolute configuration of (-)-arbusclin D have been determined to be a s shown in structure 1. The biological activities, such as cytotoxic activity toward P-388 lymphocytic leukemia, plant growth regulating activity, and antimicrobial activity of compounds 1, 3, 7, 9, 12, and 14 were also studied.


5-Epi-isospongiaquinone, a new sesquiterpene/quinone antibiotic from an Australian marine sponge, Spongia hispida.

An Australian marine sponge, Spongia hispida, has been found to contain a new sesquiterpene/quinone identified by detailed spectroscopic analysis and chemical derivatization as the antibiotic 5-epi-isospongiaquinone [3]. The complete stereostructure for 3 was determined by detailed spectroscopic analysis and chemical correlation with the known marine natural product isospongiaquinone [2]. Co-occurring with 3 was an ethylated analogue, 5-epi-homoisospongiaquinone [4], which was speculated to be an artifact of the isolation process. A revised structure 15 for the known marine metabolite, smenorthoquinone [13], is also presented.


Bioactive ergost-5-ene-3 beta, 7 alpha-diol derivatives from Pseudobersama mossambicensis.

Bioactivity-directed fractionation of the methyl ethyl ketone extract of Pseudobersama mossambicensis resulted in the isolation of ergosta-5,24(28)-diene-3 beta,7 alpha-diol [1], 24,28-epoxyergost-5-ene-3 beta,7 alpha-diol [2], and ergost-5-ene-3 beta,7 alpha,24,28-tetraol [3]. All three sterols showed selective activity towards DNA repair-deficient yeast mutants. The sterol 1 also showed cytotoxicity towards wild-type P-388 murine leukemia cells. The isolation, structural elucidation, and biological activities of these sterols are reported. The sterol 3 is most probably an artifact formed from 2 during the isolation process.


Gigantetronenin and gigantrionenin: novel cytotoxic acetogenins from Goniothalamus giganteus.

Gigantetronenin [1] and gigantrionenin [6], two new monotetrahydrofuran Annonaceous acetogenins each possessing a double bond along the hydrocarbon chain, have been isolated from the bark of Goniothalamus giganteus by the use of brine shrimp lethality for bioactivity-directed fractionation. The structures were elucidated based on spectroscopic and chemical methods. Compounds 1 and 6 both show selective and potent cytotoxicities to human tumor cells in culture as well as toxicity to brine shrimp. A known cytotoxic acetogenin, annomontacin [11], was also isolated from this plant. The biogenetic pathway of the acetogenins from G. giganteus is discussed.


Antifungal activity of meridine, a natural product from the marine sponge Corticium sp.

Meridine [1], a polycyclic alkaloid derived from the marine sponge Corticium sp., was found to inhibit the growth of Candida albicans and Cryptococcus neoformans. Activity was also observed against Trichophyton mentagrophytes and Epidermophyton floccosum. Studies of the mechanism of action of this agent have shown an inhibition of nucleic acid biosynthesis.


Motor neuron disease and polio in Scotland.

An analysis of mortality and morbidity rates for motor neuron disease (MND) in Scotland has confirmed earlier observations that the disease is more common in men and older age groups. The geographical distribution is non-uniform and related to discharge rates for all neurological diseases. Discharge and mortality rates are increasing but there has been no decline in populations who would have been vaccinated against polio.


Adult onset motor neuron disease: worldwide mortality, incidence and distribution since 1950.

This review examines the commonly held premise that, apart from the Western Pacific forms, motor neuron disease (MND), has a uniform worldwide distribution in space and time; the methodological problems in studies of MND incidence; and directions for future epidemiological research. MND is more common in men at all ages. Age-specific incidence rises steeply into the seventh decade but the incidence in the very elderly is uncertain. A rise in mortality from MND over recent decades has been demonstrated wherever this has been examined and may be real rather than due to improved case ascertainment. Comparison of incidence studies in different places is complicated by non-standardised methods of case ascertainment and diagnosis but there appear to be differences between well studied populations. In developed countries in the northern hemisphere there is a weak positive correlation between standardised, age-specific incidence and distance from the equator. There is now strong evidence for an environmental factor as the cause of the Western Pacific forms of MND. A number of clusters of sporadic MND have been reported from developed countries, but no single agent identified as responsible.


Anticoagulant treatment as a risk factor for primary intracerebral haemorrhage.

Forty one (14.2%) of 288 patients with primary intracerebral haemorrhage occurring between September 1985 and December 1989 in Central Finland were on anticoagulant treatment at the onset of symptoms. In a sample of 29,000 subjects from the same population the prevalence of anticoagulant treatment was 1.6% in those aged 40 years or older. The estimated age adjusted odds ratio of being on anticoagulant treatment at the time of primary intracerebral haemorrhage was 6.7 (95% CI from 4.5 to 9.9). The risk was highest during the first year of anticoagulation. Overtreatment (thrombotest value < 5%) was slightly more common among the patients. The haematoma volumes measured from the CT scans were similar in patients on anticoagulant treatment and those not anticoagulated. The case fatality rate during the first week and the mortality during follow up of 32 months were slightly higher, and the functional outcome slightly worse in the anticoagulated group.


Coordination of eye and head movements during smooth pursuit in patients with vestibular failure.

During pursuit of smoothly moving targets with combined eye and head movements in normal subjects, accurate gaze control depends on successful interaction of the vestibular and head movement signals with the ocular pursuit mechanisms. To investigate compensation for loss of the vestibulo-ocular reflex during head-free pursuit in labyrinthine-deficient patients, pursuit performance was assessed and compared under head-fixed and head-free conditions in five patients with isolated bilateral loss of vestibular function. Target motion consisted of predictable and unpredictable pseudo-random waveforms containing the sum of three or four sinusoids. Comparison of slow-phase gaze velocity gains under head-free and head-fixed conditions revealed no significant differences during pursuit of any of the three pseudo-random waveforms. The finding of significant compensatory eye movement during active head movements in darkness in labyrinthine-deficient patients, which were comparable in character and gain to the vestibular eye movement elicited in normal subjects, probably explains the similarity of the head-fixed and head-free responses. In two additional patients with cerebellar degeneration and vestibular failure, no compensatory eye movement response was observed, implying that the cerebellum is necessary for the generation of such responses in labyrinthine-deficient patients.


Syringobulbia: a surgical appraisal.

Syringobulbia is a term which has been clinically applied to brain stem symptoms or signs in patients with syringomyelia. Syringobulbia clefts are found on investigation or at necropsy caused by cutting outwards of the CSF under pressure from the fourth ventricle into the medulla. These should be differentiated from the ascending syringobulbia which may occur from upward impulsive fluid movements in a previously established syringomyelia. Clinical analysis of 54 patients suggests that bulbar features are most often found with neither of the above mechanisms but are due to the effects of pressure differences acting downward upon the hind-brain with consequent distortion of the cerebellum and brainstem, traction on cranial nerves or indentation of the brain-stem by vascular loops. The commonest symptoms in the 54 patients were headache (35), vertigo (27), dysphonia or dysarthria (21), trigeminal paraesthesiae (27), dysphagia (24), diplopia (16), tinnitus (11), palatal palsy (11) and hypoglossal involvement (11). Careful attention to hydrocephalus is advisable before craniovertebral surgery, but the decompression of the hindbrain and the correction of craniospinal pressure dissociation remains the mainstay of surgical treatment. The results of careful surgery are good, 45 of the 54 cases reported improvement. Most of the reported deterioration occurred in a few patients who did conspicuously badly.


The location and function of respiratory fibres in the second cervical spinal cord segment: respiratory dysfunction syndrome after cervical cordotomy.

After high cervical percutaneous cordotomy for pain in malignant disease, 12 patients died during sleep at postoperative intervals between 1 and 8 days. Nine died after a first cordotomy and three after a second (contralateral) procedure. All except one had known pulmonary disease before operation. The operated segment of the spinal cord (C2) was studied histologically after death. Superposition of lesion outlines made it possible to determine those parts of the lesioned areas common to all unilateral and bilateral cases respectively. All cases dying of presumed respiratory dysfunction syndrome had lesions involving the region of the anterolateral funiculus in the C2 segment containing "pain" fibres activated from the second to fifth thoracic dermatomes. The fibres whose destruction appeared to be responsible for respiratory dysfunction syndrome were completely intermingled with ascending "pain" fibres. The possibility of these fibres being afferent in function is discussed.


Homolateral ataxia and crural paresis: a syndrome of anterior cerebral artery territory infarction.

Five patients with superficial anterior cerebral artery territory infarcts in the paracentral area are reported, who developed a hemiparesis which was predominant in the leg, and with homolateral ataxia in the arm. A similar neurological picture was not observed in 1736 patients who were admitted over an eight year period to a primary care stroke centre with their first stroke. Involvement of corticopontine fibres at their origin, together with damage to the lower limb motor strip or underlying white matter, appears to have been the cause of a clinical syndrome (homolateral ataxia and crural paresis) which has been ascribed to lacunar infarction.


Modulation of the soleus H-reflex during pedalling in normal humans and in patients with spinal spasticity.

Soleus H-reflexes were recorded in 10 normal subjects and seven patients with spasticity caused by incomplete spinal cord injury while they pedalled on a stationary bicycle which had been modified to trigger electrical stimuli to the tibial nerve at eight precise points in the pedal cycle. Stimulus strength was adjusted to yield M-waves of constant amplitude at each pedal position. During active pedalling, all normal subjects showed modulation of the H-reflex with the amplitude being increased during the downstroke portion of the pedal cycle and the reflex suppressed or absent during the upstroke. This modulation was not present during passive pedalling, with the experimenter cranking the pedals by hand, or when the pedals were locked at each of the eight positions. In five of the seven patients with spasticity, there was reduced or absent modulation of the H-reflex during active pedalling and the reflex remained large during pedal upstroke. It is concluded that descending motor commands that produce patterned voluntary activity during pedalling normally cause cyclical gating of spinal reflexes by either presynaptic or postsynaptic inhibitory mechanisms. Loss of supraspinal control over these spinal inhibitory systems could result in failure to produce appropriate suppression of reflexes during patterned voluntary movements such as pedalling or walking, and may be an important factor contributing to the functional disability in spasticity.


Neuropsychiatric systemic lupus erythematosus in elderly people: a case series.

Five elderly patients presenting with neuropsychiatric systemic lupus erythematosus were referred to the sectorised psychiatry service of the department of health care of the elderly. They represented 2% of patients admitted over a period of two years. Two patients presented with a subacute confusional state, two with dementia, and one with depression. Three patients responded well to treatment. This suggests that systemic lupus erythematosus (SLE) is more common in elderly people than was originally thought and is a potentially treatable cause of organic brain disorder. The absence of reports of elderly patients with SLE is likely to be due to the continued application of the American Rheumatism Association's revised 1982 classification criteria, which are inappropriate for this population.


Movement disorders in astrocytomas of the basal ganglia and the thalamus.

In a series of 225 patients with astrocytomas (grades I-IV) of the basal ganglia and the thalamus, 20 had a movement disorder. In all patients the histological diagnosis was verified by stereotactic biopsy. Tremor was observed in twelve patients, dystonia in eight, chorea in three, and chorea/ballismus and myoclonus in one. The tumour involved the thalamus in 16 patients. Corticospinal tract dysfunction was evident in 70% of the patients with movement disorders and in 73% of those without. Demographic, clinical, histological and neuroradiological data of the patients with a movement disorder were compared with the data of patients without. CT data yielded no differences with respect to the involvement of anatomical structures. Movement disorders were significantly associated with low-grade astrocytomas.


Material-specific memory loss in probable Alzheimer's disease.

This study extends previous work analysing functional dissociations occurring in patients with Alzheimer's disease (AD) by demonstrating that material-specific memory loss is common. The pattern of neuropsychological dysfunction in 191 patients with probable AD was examined and 13% presented with material-specific memory loss. Thirteen patients had impaired immediate verbal recall, but normal non verbal recall and 12 had impaired non verbal recall and normal verbal memory. These patterns appeared to be related to a specific memory deficit and were probably not secondary to associated cognitive impairments. These data confirm earlier observations that the memory defect in AD can be material-specific, and suggest that these patterns of impairment should be viewed as a focal sparing of function.


A study of regional cerebral blood flow and cognitive performance in Alzheimer's disease.

Thirty five patients with dementia of the Alzheimer type (DAT) and 35 controls matched for age, sex and handedness were investigated using single photon emission computer tomography (SPECT) with 99m technetium HMPAO. Regional cerebral blood flow (rCBF) was assessed semi-quantitatively in 18 cortical and 4 subcortical areas by normalising mean information density in each region to cerebellar mean information density. Analysis revealed significantly reduced rCBF to temporal, parietal, frontal and left occipital cortex in the patients whilst blood flow to subcortical areas showed no differences between the 2 groups. In addition, significant left-sided cortical hypoperfusion was seen in the DAT group but not in controls. When patients were sub-divided on the basis of disease severity, those with mild disease showed temporal, parietal and left frontal changes with more severely affected patients also showing right frontal and left occipital involvement. rCBF patterns did not distinguish between presenile and senile onset cases once duration and severity of illness were controlled. Eight cortical areas were also rated visually for perfusion deficits on a simple 4 point scale. Perfusion deficits were detected in 34 of 35 patients but in only 4 of 35 controls. In the DAT group significant correlations were found between many of the neuropsychological tests used and rCBF. Memory correlated with left temporal activity, praxis, perception, object assembly and block design with right parietal activity and language with activity throughout the left hemisphere. Significant correlations were also seen between subcortical and cortical blood flow, possibly explaining the correlations observed between many of the neuropsychological tests and thalamic blood flow.


Early diagnosis and treatment of spinal epidural metastasis in breast cancer: a prospective study.

This prospective study evaluated the usefulness of myelography in breast cancer patients who present with radiculopathy or myelopathy. A total of 124 consecutive myelograms were performed in 100 patients. Epidural metastasis (EM) was diagnosed in 67 myelograms (54%). Multiple epidural metastases were diagnosed in 15 (22%) of those, resulting in a total of 87 epidural lesions. A complete block was found in 13 EM (15%) and an incomplete block in 14 EM (16%). Clinical data could not predict the site of EM in 29 cases (33%). Fifteen asymptomatic EM were detected in myelograms with multiple EM. Plain radiographs were of no value in determining the site of EM in 29 cases (33%), including 13 cases (15%) without vertebral metastasis at the site of EM. Treatment consisted of radiotherapy (RT) with or without systemic treatment in 52 cases (80%), systemic treatment alone in 11 cases (17%) and surgery in two patients (3%). Clinical improvement was noticed in 72%, no change in 13%, and deterioration in 15%. No difference in response was noticed between RT and systemic therapy. Before treatment 21% and after treatment 15% of the patients could not walk. The one year survival was 42%. The ambulatory status at presentation was the most important prognostic factor. Examination of the spinal fluid, obtained at myelography, disclosed meningeal carcinomatosis in 9% of the patients. Imaging of the whole spinal canal with cytological examination of the spinal fluid is recommended in breast cancer patients suspected of epidural tumour with features of radiculopathy or myelopathy, irrespective of further clinical data and plain spinal radiographs.


A further British case of growth hormone induced Creutzfeldt-Jakob disease.

Transmission of Creutzfeldt-Jakob disease (CJD) from cadaveric growth hormone injections had previously been reported in 7 cases, including one from Britain. As a result, the treatment was abandoned in 1985 and superceded by safer recombinant DNA growth hormone injections. Recent reports now record the number of cases worldwide as 23, but with the incubation period being measured in years, new cases of CJD can still present. We give a detailed report of one of the recent cluster of British cases and aim to highlight the problem to clinicians who may encounter further patients with cadaveric growth hormone induced CJD.


Tardive dyskinesia presenting as severe dysphagia.

A case of tardive dyskinesia presenting with severe dysphagia as the predominant feature is described. Diagnosis was delayed because clinically apparent orofacial dyskinetic movements were minimal. The symptoms resolved following the cessation of neuroleptic medication.


Prolactin secreting pituitary carcinoma.

A man with a prolactin secreting pituitary carcinoma was treated by surgery and radiotherapy. Persistent hyperprolactinaemia partially responded to oral bromocriptine for four years. Serum prolactin then rose considerably with rapid, invasive tumour recurrence. Cytotoxic chemotherapy halted tumour progression for twelve months before fatal spread throughout the brain. Failure to normalise serum prolactin with bromocriptine may precede an aggressive course in patients with prolactinoma.


Frontal lobe cerebral aneurysm rupture presenting as psychosis.

A 23 year old male with acute onset of blunted affect, looseness of associations and auditory hallucinations presented to a tertiary care hospital 10 days after development of symptoms. Before transfer, the patient received a diagnosis of schizophreniform disorder and treatment with haloperidol was started which resulted in moderate improvement. Examination led to detection of a ruptured cerebral aneurysm in the left frontal lobe. Evacuation of the haematoma and repair of the aneurysm resulted in nearly complete resolution of symptoms. The rare incidence of acute aneurysm rupture, presenting in the case described, demonstrates the importance of a complete neurological examination in the evaluation of acute mental status changes.


In vitro interactions of aminoglycosides with imipenem or ciprofloxacin against aminoglycoside resistant Acinetobacter baumannii.

The in vitro interactions between gentamicin, tobramycin, netilmicin and amikacin with imipenem and ciprofloxacin were evaluated by the killing curve technique against 20 clinical isolates of Acinetobacter baumannii highly resistant to aminoglycosides which were susceptible or moderately susceptible to imipenem and resistant or moderately susceptible to ciprofloxacin. Imipenem enhanced killing by gentamicin, tobramycin, netilmicin and amikacin in tests with 9, 12, 10 and 15 strains (45-75%) while ciprofloxacin with 3, 7, 5 and 6 strains (15-35%) respectively. Interaction results were influenced by the height of aminoglycoside minimum bactericidal concentrations (MBCs) but were independent of imipenem or ciprofloxacin MBCs and the presence of aminoglycoside modifying enzymes. It is concluded that enhanced killing after aminoglycoside interaction with imipenem or ciprofloxacin versus A. baumannii cannot be predicted but it should be carefully tested in vitro. The in vivo significance of the reported findings mandates clinical studies in humans.


Hepatic and intestinal effects of flurithromycin and erythromycin in the rat.

The effects of flurithromycin (30-100 mg/kg p.o.), a fluorinated macrolide, on rat hepatic enzymes and intestinal microflora have been compared with those of equal doses of erythromycin. This latter drug significantly decreases cytochrome b5, cytochrome P-450 and aminopyrine N-demethylase and moderately influences intestinal microbial flora. Flurithromycin showed almost opposite characteristics, with no hepatic interaction and marked effects on some bacterial species (e.g. Bacteroides) known to facilitate the colonization of pathogenetic bacteria.


Correlation between the in vivo and in vitro antimicrobial properties of commercially available mouthwash preparations.

The effectiveness of six commercially available mouthwashes against common buccal organisms was studied. The minimum inhibitory concentrations (MIC) for two of the studied mouthwashes (Corsodyl and Oraldene) against buccal organisms were determined in Todd Hewitt medium with or without 5% serum. The concentration of the active substance in these two mouthwashes was in excess of the corresponding MIC. When the medium was supplemented with serum, lower MIC values were observed. Kill-time determinations, used at half the concentration of the normal preparation, revealed a rapid lethal effect for all tested mouthwashes. The slowest lethal effect was observed with Fluocaril mouthwash. When mouthwashes were tested in volunteers, an immediate significant fall in salivary bacterial counts was produced by all except Fluocaril. With the latter mouthwash the decrease was significant 2-30 minutes after rinsing. The bacterial levels returned to pre-rinse levels after 30 minutes for Listerine, after 90 minutes for both Oraldene and Mint and after 180 minutes for Corsodyl, Fluocaril and Sansilla mouthwashes. The results indicate that there is a good correlation between in vivo efficacy and in vitro determination of all mouthwash preparations.


Effect of minocycline on the sperm count and activity in infertile men with high pus cell count in their seminal fluid.

Twenty-five infertile males with 5 or more pus cells per 1000 x field in their seminal fluid were randomly assigned to treatment with minocycline 200 mg daily for one (Group A) or two (Group B) weeks. At the end of the treatment period a statistically significant reduction of pus cells, and a statistically significant increase in the sperm count and the motile sperm were observed (Wilcoxon matched-pairs signed-ranks test, p < 0.01). No statistically significant differences were observed between the two groups (Mann Whitney U test). No toxicity was reported. In conclusion, minocycline improves the seminal indices, in infertile males with high pus cell count in their seminal fluid.


Experimental studies of immunotoxicity of a photosensitizing agent (Photofrin II) in mice.

Immunotoxicity studies have been performed on the photosensitizing agent Photofrin II (PHFR), a porphyrin derivative used in photodynamic therapy. Hybrid CD2F1 (H-2d/H-2d) or inbred C57Bl/6 (H-2b) male mice were injected with graded doses of the agent (from 1.2 to 12 mg/Kg ip) on day -5, -3 and -1 before assays. The animals, or spleen cells collected from them on day 0 with respect to PHFR treatment, were tested for: a) competence of producing GVHD upon cell transfer into allogeneic, immunosuppressed recipients; b) graft response against challenge with allogeneic lymphoma cells; c) delayed-type hypersensitivity (DTH) against sheep red blood cells; d) in vitro response to mitogens; e) NK cell activity; f) in vitro generation of alloreactive cytotoxic T lymphocytes (CTL); g) resistance against the challenge of a sublethal dose of Pseudomonas aeruginosa. Moreover the LD50 of the drug given ip has been determined in male CD2F1 mice. The results show that PHFR, even at the highest doses used, does not affect most of the immunological parameters studied, except for a marginal inhibition of CTL generation and increment in proliferative responses to Con A or LPS. These data along with parallel studies performed by our group on human models in vitro, showing increased susceptibility of PHFR-treated tumors to NK or LAK effector cells, point out that PHFR, in the absence of systemic photoactivation, is essentially non-immunotoxic in vivo and could render tumor cells more susceptible to natural immunity.


Treatment of chronic hepatitis C with recombinant interferon alpha 2b.

The authors studied 70 patients affected by chronic hepatitis C where diagnosis had been made by clinical and histological tests. Intramuscular recombinant alpha 2b interferon (3 x 10(6)) was administered to 35 patients every second evening for 6 months, whereas the other 35 received aspecific treatment. Our results revealed normalization of transaminase in 57% of the patients, with distinct improvement of their clinical and histological pictures. All patients on interferon were followed up for a six-month drug free period, after which the disease reappeared in 50% of the responders.


Octreotide treatment in secretory and cyrptosporidial diarrhea in patients with acquired immunodeficiency syndrome (AIDS): clinical evaluation.

Our objective was to evaluate the efficacy of octreotide in the treatment of AIDS patients with persistent diarrhea refractory to conventional therapy. We have treated 11 patients with AIDS related diarrhea (M/F-5/2, mean age 28 +/- 3 yr). The stool volume was in all pts > or = 21/24h. In 4 pts the diarrhea was secondary to cryptosporidium infection (Group A); in 7 pts the reason for the diarrhea could not be identified (Group B). Octreotide was administered in subcutaneous escalation doses, from 50 micrograms q8h to a maximum dose of 500 micrograms q8h. The minimal dose controlling symptoms was maintained for 21 days. In all patients stool volume and frequency decreased significantly. Group A pts were "partial responders" (stool 50% of initial daily volume); group B patients were "complete responders" (stools < 250-300 ml/day). Drug suspension resulted in a prompt return of diarrhea, especially in group A and in these patients, the cryptosporidium was continuously eliminated in the stool. With octreotide therapy there was a reduction in stool volume and frequency; whether this treatment is effective as long-term therapy for this AIDS manifestation is unknown.


Evaluation of the in vitro antiproliferative properties of four novel anthracyclines YM1, 3, 4 and 6 in human leukemia cell lines.

The antitumor activity of novel doxorubicin analogues YM1, YM3, YM4 and YM6 was evaluated against drug sensitive U937 monocytic leukemia and CCRF-CEM lymphoid leukemia cell lines, as well as drug resistant CEM/VLB100 lymphoid multidrug resistant leukemia cell line by a [3H]thymidine incorporation assay. Different antileukemic activities of these new anthracyclines were observed in our studies. These novel anthracyclines produced a dose- and time-dependent inhibition in all the leukemic cell lines tested, while YM1 and YM3 were more effective than YM4 and YM6 against all the leukemic cell lines. The antitumor activity of all these novel analogues was lower than that of doxorubicin or epidoxorubicin in drug sensitive leukemic cells. The relative resistance values (IC50 of resistant cell line/IC50 of sensitive parental cell line) of YM1, 3, 4 and 6 were 27, 7, 5 and 14 respectively. These were lower than the resistance values for ADM and EDR which were 45 and 40 respectively. YM3 had a similar antileukemic activity against the CEM/VLB100 drug resistant leukemic cell line to ADM or EDR with a lower relative resistance value and a slightly increased IC50 value. Our results suggest that YM3 may be used in high dose for the clinical treatment of leukemias with possible less cardiotoxicity as well as less drug resistance.


GnRH analogs in gynecological oncology: a review.

Chronic GnRH analogs (GnRH-A) administration has proven to be effective for the control of some hormone-dependent tumors. GnRH-A are now in the standard treatment of prostatic cancer. In the present paper experimental and clinical data on the use of GnRH-A in gynecologic oncology are reviewed in order to identify a possible role in the therapy of breast, endometrial and ovarian cancer. Besides the indirect hormonal effect of GnRH-A, mediated by the suppression of gonadal steroidogenesis, in vitro evidence suggests a direct anti-proliferative action involving autocrine-paracrine regulation of cellular function. In advanced or recurrent breast cancer objective responses were observed in 157 out of 378 premenopausal patients (41%) and in 18 out of 166 postmenopausal women (10%). In ovarian cancer complete and partial responses were observed in 14 out of 121 (11%). At present, data on advanced endometrial carcinoma are limited: only 18 treated patients are reported, of whom 7 responded (38.8%). However, in general, most of the responses observed were transient. Thus, so far, the use of GnRH-A in gynecologic oncology has to be considered for palliation, after the failure of other better understood treatment modalities. The possible use of GnRH-A as an adjuvant is still under investigation.


Chemotherapy-induced amenorrhea and other clinical and pathological parameters in the prognosis of breast cancer patients.

147 stage II pre- and perimenopausal breast cancer patients were treated with cyclophosphamide-methotrexate-5-fluorouracil (CMF)- based adjuvant regimens. 103 (72%) patients became amenorrheic during or immediately after the end of the chemotherapy program. Univariate analyses for age, menstrual status, nodal involvement, grading, estrogen and progesterone receptor status indicated no correlation between induction of amenorrhea and a significant prolongation of overall and disease-free survival. Multivariate analyses confirmed that young age at diagnosis, increasing number of infiltrated nodes, negative progesterone receptor status and grade 3 tumors are associated with a worse prognosis. Our results suggest that no benefit is expected in women with drug induced amenorrhea after CMF adjuvant treatment.


The antiemetic efficacy and the cost-benefit ratio of ondansetron calculated with a new approach to health technology assessment (real cost-benefit index).

In a phase II study including 80 patients treated with highly emetic drugs such as cisplatin, carboplatin or cyclophosphamide > 600 mg/day) we confirmed the potential of ondansetron to prevent cancer chemotherapy- related acute nausea and vomiting. With a total dose of 19.0-37.3 mg ondansetron we achieved 82%-100% acute (0-24 hours) vomiting free patients. Using ondansetron for the prevention of acute nausea and vomiting increases the total chemotherapy costs by 6%. The real cost-benefit ratio for the treatment of acute nausea and vomiting shows better values for ondansetron than for all other recommended regimens.


Altered patterns of reflex excitability subsequent to contusion injury of the rat spinal cord.

1. The present study investigated regulation of reflex excitability after experimental contusion injury of the spinal cord. 2. Four measures of H-reflex excitability were evaluated in normal rats and at 6, 28, and 60 days after contusion injury at the T8 level: 1) reflex thresholds, 2) slope of the reflex recruitment curves, 3) maximal plantar H-reflex/maximal plantar M-response (Hmax/Mmax) ratios, and 4) rate-sensitive depression (i.e., the decrease in reflex magnitude relative to repetition rate). 3. Tested as a function of the afferent volley magnitude, the thresholds for reflex initiation fell progressively subsequent to contusion injury. No change was observed at 6 days postinjury, and the decrease at 28 days was not significant. However, by 60 days postinjury, the threshold had decreased by 23% of the maximal afferent volley, and this decrease was significant, [analysis of variance (ANOVA, P < or = 0.01)]. 4. Hmax/Mmax ratios elicited in postcontusion animals at 0.3 Hz were not significantly different from those recorded in normal animals. 5. The slopes of the recruitment curves were markedly reduced subsequent to contusion injury. The decrease was greatest at 6 days postinjury. Although some recovery toward normal occurred at 28 and 60 days postinjury, the slopes of recruitment curves in postcontusion animals remained significantly decreased. 6. H-reflexes elicited at 1-5 Hz were less sensitive to rate depression in postcontusion animals than in normal animals at the same respective frequencies. The decrease was progressive in onset, becoming significant by 28 days postinjury, and of an enduring nature, i.e., still significantly different from normal in the reflexes tested 60 days postinjury. 7. Rate sensitivity of the tibial nerve monosynaptic reflex (MSR) was also compared in normal and postcontusion animals. Rate sensitivity of the tibial MSRs was significantly reduced at 28 and 60 days post-contusion, compared with normal animals. 8. These data indicate that significant changes in lumbar reflex excitability result from midthoracic contusion injury of the spinal cord. These changes include reflex threshold, slope of recruitment, and rate-sensitive depression. Although recruitment slope was most altered in the shortest postinjury interval tested, followed by some recovery, the other changes were progressive in onset and enduring in duration.


Topography of excitatory bandwidth in cat primary auditory cortex: single-neuron versus multiple-neuron recordings.

1. The spatial distribution of the sharpness of tuning of single neurons along the dorsoventral extent of primary auditory cortex (AI) was studied. A sharpness of tuning gradient was initially obtained with multiple-unit recordings, and in combination with the cochleotopic organization, served as a frame of reference for the locations of single neurons. The frequency selectivity or "integrated excitatory bandwidth" of multiple units varied systematically along the dorsoventral extent of AI. The most sharply tuned unit clusters were found at the approximate center of the dorsoventral extent. A gradual broadening of the integrated excitatory bandwidth in both dorsal and ventral directions was consistently seen. 2. The multiple-unit measures of the bandwidth 10 (BW10) and 40 dB (BW40) above minimum threshold, pooled across several animals and expressed in octaves, were similar to those described within individual cases in cats. As in the individual animals, the bandwidth maps were V shaped with minima located at the approximate center of the dorsal-ventral extent of AI. The location of the minimum in the multiple-unit bandwidth map (i.e., the most sharply tuned area) was used as a reference point to pool single-neuron data across animals. 3. For single neurons, the dorsal half of the BW40 distribution showed a gradient paralleling that found for multiple units. For both single and multiple units, the average excitatory bandwidth increased at a rate of approximately 0.27 octaves/mm from the center of AI toward the dorsal fringe. Differing from the dorsal half of AI, the ventral half of AI showed no clear BW40 gradient for single units along its dorsoventral extent. At 40 dB above minimum threshold, most ventral neurons encountered were sharply tuned. By contrast, the multiple-unit BW40 showed a gradient similar to the dorsal half with 0.23 octaves/mm increasing from the center toward the ventral border of AI. 4. For single neurons, BW10 showed no clear systematic spatial distribution in AI. Neither the dorsal nor the ventral gradient was significantly different from zero slope, although the dorsal half showed a trend toward increasing BW10s. Contrasting single neurons, both dorsal and ventral halves of AI showed BW10 slopes for multiple units confirming a V-shaped map of the integrated excitatory bandwidth within the dorsoventral extent of AI. 5. On the basis of the distribution of the integrated (multiple-unit) excitatory bandwidth, AI was parceled into three regions: the dorsal gradient, the ventral gradient, and the central, narrowly tuned area.(ABSTRACT TRUNCATED AT 400 WORDS)


Effect of velocity and mechanical history on the forces of motor units in the cat medial gastrocnemius muscle.

1. Two fundamental aspects of the dynamic behavior of motor units of the cat medial gastrocnemius (MG) muscle were measured. Force-velocity (FV) relationships were measured with the use of constant velocity shortening and lengthening movements. Effects of mechanical history were assessed via comparisons of forces immediately after or during slow movements with standard isometric forces. Isometric force-length (FL) relations were also measured, and the effect of different stimulation rates on both FV and FL data was assessed. 2. Prior or concurrent movement greatly potentiated motor-unit force, but this movement potentiation was highly dependent on the amplitude of the unit's force. The smallest twitch forces of type S units (< 10 mN) were potentiated more than threefold, but no potentiation occurred for unit forces > 200 mN. It was tentatively concluded that movement potentiation may play little role in normal movements because it does not occur at forces > 1% of maximal isometric force of the MG. 3. During shortening, the normalized FV relations of type S units were relatively steeper than those of type FR or FF units. For lengthening, there was no evident relation between FV steepness and motor-unit type. 4. Stimulation rate affected both the FV and FL relationships of the motor units. The peak of the FL relationship (Lo) clearly shifted to shorter muscle lengths as stimulation rate was increased. The steepness of the FV relationship for shortening was decreased by increasing stimulation rate, but this effect was modest. 5. The shift in motor-unit Lo and the differences in motor-unit FV relationships were hypothesized to play significant roles during normal motor behavior. Realistic computer simulations of FL and FV functions for a population of motor units undergoing normal steady-state recruitment and rate modulation supported these hypotheses. As the level of simulated neural drive increased, the population Lo shifted to considerably shorter lengths, and the normalized FV function became much less steep. The significance of these results for models of muscle are discussed.


Effects of reversible blockade of basal ganglia on a voluntary arm movement.

1. The effects of a reversible blockade of basal ganglia were examined in two monkeys trained to perform a visually guided, step-tracking arm movement around the elbow joint. To block glutamatergic excitation, kynurenate (a glutamate antagonist) was locally injected into the putamen and the external segment (GPe) and the internal segment (GPi) of the globus pallidus contralateral to the arm tested. Muscimol [a gamma-aminobutyric acid (GABA) agonist] was also used to suppress neuronal activity in these structures. The drugs were injected in the arm area of the putamen, which was identified by microstimulation or by recording neural activity. For the GPe and GPi, injections were made into the area medioventral to the arm area of the putamen. 2. The blockade of the putamen caused abnormal braking of the arm movements. The first step of the movement became hypometric, and multiple steps were necessary to reach the target. The electromyographic (EMG) analysis revealed an increase of burst activity in the antagonist muscles and a decrease of that in the agonist muscles at the fast movements. The tonic activity increased in the extensor muscles during a holding period. 3. The blockade of the GPi caused dysmetric movements. Amplitude and peak velocity of the first step of movement largely fluctuated among trials. It became difficult for the animal to brake and adjust its arm onto the target. 4. The blockade of the GPe caused a flexion posture at the elbow joint of the contralateral arm. The tonic activity of the flexor muscles increased. Cocontraction of the agonist and antagonist muscles was also observed. 5. These results suggest that the putaminopallidal system of the basal ganglia contributes to both of two motor functions: 1) static control to maintain the posture with tonic muscle activity, and 2) dynamic control to enable fast movements.