[Adverse effects of oncohaematological immunotherapy: implications for Primary Care and continuity of care]. / Efectos adversos de la inmunoterapia oncohematológica: implicaciones para la Atención Primaria y la continuidad asistencial.

Antineoplastic treatment is increasingly being used due to the boom in immunotherapy, which translates into a constant change in the paradigm of the tumour approach. Immunotherapy in some tumours is a first line therapy and has drastically changed the prognosis of many of them. It has some very specific adverse effects, arising from the inhibition of the mechanisms of control of the immune response. The spectrum of toxicities is complex, and very different from that of conventional chemotherapy. This implies that these must be known by the various professionals of the different levels of care that can potentially provide care to cancer patients. A multidisciplinary and coordinated approach is required to enable them to be diagnosed and treated early, representing a clear example of the essential continuity of care, in which Primary Care plays a key role.

Efectos adversos de la inmunoterapia oncohematológica: implicaciones para la Atención Primaria y la continuidad asistencial / Adverse effects of oncohaematological immunotherapy: implications for Primary Care and continuity of care

El tratamiento antineoplásico está experimentando una importante evolución debido al auge de la inmunoterapia, lo que se traduce en un constante cambio en el paradigma del abordaje tumoral. La inmunoterapia en algunos tumores es un tratamiento de primera elección y ha permitido cambiar drásticamente el pronóstico de muchos de ellos. Presenta unos efectos adversos muy específicos, derivados de la inhibición de los mecanismos de control de la respuesta inmune. El espectro de toxicidades es complejo y muy diferente al de la quimioterapia convencional. Esto implica que deban ser conocidas por los diversos profesionales de los diferentes niveles asistenciales que potencialmente pueden atender a los pacientes oncológicos. Se requiere de un enfoque multidisciplinar y coordinado que permita diagnósticos y tratamientos precoces de las mismas, representando un claro ejemplo de la imprescindible continuidad asistencial, en la que la Atención Primaria posee un papel central

Antineoplastic treatment is increasingly being used due to the boom in immunotherapy, which translates into a constant change in the paradigm of the tumour approach. Immunotherapy in some tumours is a first line therapy and has drastically changed the prognosis of many of them. It has some very specific adverse effects, arising from the inhibition of the mechanisms of control of the immune response. The spectrum of toxicities is complex, and very different from that of conventional chemotherapy. This implies that these must be known by the various professionals of the different levels of care that can potentially provide care to cancer patients. A multidisciplinary and coordinated approach is required to enable them to be diagnosed and treated early, representing a clear example of the essential continuity of care, in which Primary Care plays a key role

Interaction in hospitalized patient-led and staff-led psychotherapy groups.

Psychotic patients' participation in two kinds of inpatient group therapy, one staff-led, and the other patient-led with staff observing, revealed that patients talked more in the patient-led group than in the traditional staff-led group. Discussion explored the importance of peer, self-help influences in groups for stimulating psychotic patients to take more responsibility for themselves and other patients.

[A rare bone disease, but one not to be ignored: osteopathia striata]. / Une affection osseuse rare, mais à ne pas méconnaître: l'ostéopathie striée.

A case of osteopathia striata is reported, and this rare bone dysplasia reviewed. Normally asymptomatic, diagnosis of the disorder depends upon the finding of characteristic bone striation on radiological examination. A rarely isolated lesion, osteopathia striata is generally associated with other affections, which require systematic investigation in cases demonstrating typical radiological anomalies.

[Ultrasonic inspection of the permeability of surgical portacaval shunts]. / Contrôle échotomographique de la perméabilité des dérivations porto-caves chirurgicales.

Ultrasonography was used to evaluate the patency of portocaval shunts in 9 patients: 2 with spleno-renal anastomosis, 4 with portocaval truncular anastomosis, 2 with mesenteric-caval shunt and 1 with atypical shunt. The shunt count be demonstrated in 7 of these 9 patients. Angiography was performed in 6 cases and confirmed the results of ultrasonography--a finding favourable to the latter method and in agreement with those of other authors. However, the usefulness of ultrasonography varies according to the type of shunt created, as shown by our own experience and by published reports: 70% of portocaval truncular shunts, 65% of spleno-renal shunts and 46% of mesenteric-caval shunts are demonstrable by ultrasounds, these variations being due to differences in location and accessibility to the ultrasonic examination. It ultrasonography fails to display the anastomosis, it may provide indirect signs of patency. In addition to being harmless and relatively inexpensive, ultrasonography is a valuable method for evaluating portocaval shunts. It can easily be repeated and its results need not be confirmed by angiography.

Control of the shift from homolactic acid to mixed-acid fermentation in Lactococcus lactis: predominant role of the NADH/NAD+ ratio.

During batch growth of Lactococcus lactis subsp. lactis NCDO 2118 on various sugars, the shift from homolactic to mixed-acid metabolism was directly dependent on the sugar consumption rate. This orientation of pyruvate metabolism was related to the flux-controlling activity of glyceraldehyde-3-phosphate dehydrogenase under conditions of high glycolytic flux on glucose due to the NADH/NAD+ ratio. The flux limitation at the level of glyceraldehyde-3-phosphate dehydrogenase led to an increase in the pool concentrations of both glyceraldehyde-3-phosphate and dihydroxyacetone-phosphate and inhibition of pyruvate formate lyase activity. Under such conditions, metabolism was homolactic. Lactose and to a lesser extent galactose supported less rapid growth, with a diminished flux through glycolysis, and a lower NADH/NAD+ ratio. Under such conditions, the major pathway bottleneck was most probably at the level of sugar transport rather than glyceraldehyde-3-phosphate dehydrogenase. Consequently, the pool concentrations of phosphorylated glycolytic intermediates upstream of glyceraldehyde-3-phosphate dehydrogenase decreased. However, the intracellular concentration of fructose-1,6-bisphosphate remained sufficiently high to ensure full activation of lactate dehydrogenase and had no in vivo role in controlling pyruvate metabolism, contrary to the generally accepted opinion. Regulation of pyruvate formate lyase activity by triose phosphates was relaxed, and mixed-acid fermentation occurred (no significant production of lactate on lactose) due mostly to the strong inhibition of lactate dehydrogenase by the in vivo NADH/NAD+ ratio.

Physiology of pyruvate metabolism in Lactococcus lactis.

Lactococcus lactis, a homofermentative lactic acid bacterium, has been studied extensively over several decades to obtain sometimes conflicting concepts relating to the growth behaviour. In this review some of the data will be examined with respect to pyruvate metabolism. It will be demonstrated that the metabolic transformation of pyruvate can be predicted if the growth-limiting constraints are adequately established. In general lactate remains the major product under conditions in which sugar metabolism via a homolactic fermentation can satisfy the energy requirements necessary to assimilate anabolic substrates from the medium. In contrast, alternative pathways are involved when this energy supply becomes limiting or when the normal pathways can no longer maintain balanced carbon flux. Pyruvate occupies an important position within the metabolic network of L. lactis and the control of pyruvate distribution within the various pathways is subject to co-ordinated regulation by both gene expression mechanisms and allosteric modulation of enzyme activity.

Pyruvate metabolism in Lactococcus lactis is dependent upon glyceraldehyde-3-phosphate dehydrogenase activity.

Modification of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity from Lactococcus lactis was undertaken during batch fermentation on lactose, by adding various concentrations of iodoacetate (IAA), a compound which specifically inhibits GAPDH at low concentrations, to the culture medium. As IAA concentration is increased, GAPDH activity diminishes, provoking a decrease of both the glycolytic flux and the specific growth rate. This control exerted at the level of GAPDH was due partially to IAA covalent fixation but also to the modified NADH/NAD+ ratio. The mechanism of inhibition by NADH/NAD+ was studied in detail with the purified enzyme and various kinetic parameters were determined. Moreover, when GAPDH activity became limiting, the triose phosphate pool increased resulting in the inhibition of pyruvate formate lyase activity, while the lactate dehydrogenase is activated by the high NADH/NAD+ ratio. Thus, modifying the GAPDH activity provokes a shift from mixed-acid to homolactic metabolism, confirming the important role of this enzyme in controlling both the flux through glycolysis and the orientation of pyruvate catabolism.

Regulation of pyruvate metabolism in Lactococcus lactis depends on the imbalance between catabolism and anabolism.

Two strains of Lactococcus lactis ssp. cremoris, MG 1820 and MG 1363, which differed by the presence or absence of the lactose plasmid, respectively, were cultivated in batch-mode fermentation on lactose as carbon substrate. A correlation between the rate of sugar consumption, the growth rate, and the type of metabolism was observed. The MG 1820 strain grew rapidly on lactose and homolactic fermentation occurred. The major regulating factor was the NADH/NAD(+) ratio proportional to the catabolic flux, which inhibited glyceraldehyde-3-phosphate dehydrogenase activity. This control led to an increase in metabolite concentration upstream of this enzyme, glyceraldehyde-3-phosphate and dihydroxyacetone-phosphate, and inhibition of pyruvate formate lyase activity, while lactate dehydrogenase was strongly activated by the high coenzyme ratio. The contrary was observed during growth of the MG 1363 strain. Further investigation during growth of L. lactis ssp. lactis NCDO 2118 on galactose as carbon substrate and on various culture media enabling the growth rate to proceed at various rates demonstrated that the relative flux between catabolism and anabolism was the critical regulating parameter rather than the rate of glycolysis itself. In a minimal medium, where anabolism was strongly limited, the rate of sugar consumption was reduced to a low value to avoid carbon and energy waste. Despite this low sugar consumption rate, the catabolic flux was in excess relative to the anabolic capability and the NADH/NAD+ ratio was high, typical of a situation of nonlimiting catabolism leading to a homolactic metabolism.

Glucose metabolism and regulation of glycolysis in Lactococcus lactis strains with decreased lactate dehydrogenase activity.

The distribution of carbon flux at the pyruvate node was investigated in Lactococcus lactis under anaerobic conditions with mutant strains having decreased lactate dehydrogenase activity. Strains previously selected by random mutagenesis by H. Boumerdassi, C. Monnet, M. Desmazeaud, and G. Corrieu (Appl. Environ. Microbiol. 63, 2293-2299, 1997) were found to have single punctual mutations in the ldh gene and presented a high degree of instability. The strain L. lactis JIM 5711 in which lactate dehydrogenase activity was diminished to less than 30% of the wild type maintained homolactic metabolism. This was due to an increase in the intracellular pyruvate concentration, which ensures the maintained flux through the lactate dehydrogenase. Pyruvate metabolism was linked to the flux limitation at the level of glyceraldehyde-3-phosphate dehydrogenase, as previously postulated for the parent strain (C. Garrigues, P. Loubière, N. D. Lindley, and M. Cocaign-Bousquet (1997) J. Bacteriol. 179, 5282-5287, 1997). However, a strain (L. lactis JIM 5954) in which the ldh gene was interrupted reoriented pyruvate metabolism toward mixed metabolism (production of formate, acetate, and ethanol), though the glycolytic flux was not strongly diminished. Only limited production of acetoin occurred despite significant overflow of pyruvate. Intracellular metabolite profiles indicated that the in vivo glyceraldehyde-3-phosphate dehydrogenase activity was no longer flux limiting in the Deltaldh strain. The shift toward mixed acid fermentation was correlated with the lower intracellular trioses phosphate concentration and diminished allosteric inhibition of pyruvate formate lyase.

Construction and analysis of bacterial artificial chromosome libraries from a marine microbial assemblage.

Cultivation-independent surveys of ribosomal RNA genes have revealed the existence of novel microbial lineages, many with no known cultivated representatives. Ribosomal RNA-based analyses, however, often do not provide significant information beyond phylogenetic affiliation. Analysis of large genome fragments recovered directly from microbial communities represents one promising approach for characterizing uncultivated microbial species better. To assess further the utility of this approach, we constructed large-insert bacterial artificial chromosome (BAC) libraries from the genomic DNA of planktonic marine microbial assemblages. The BAC libraries we prepared had average insert sizes of 80 kb, with maximal insert sizes > 150 kb. A rapid screening method assessing the phylogenetic diversity and representation in the library was developed and applied. In general, representation in the libraries agreed well with previous culture-independent surveys based on polymerase chain reaction (PCR)amplified rRNA fragments. A significant fraction of the genome fragments in the BAC libraries originated from as yet uncultivated microbial species, thought to be abundant and widely distributed in the marine environment. One entire BAC insert, derived from an uncultivated, surface-dwelling euryarchaeote, was sequenced completely. The planktonic euryarchaeal genome fragment contained some typical archaeal genes, as well as unique open reading frames (ORFs) suggesting novel function. In total, our results verify the utility of BAC libraries for providing access to the genomes of as yet uncultivated microbial species. Further analysis of these BAC libraries has the potential to provide significant insight into the genomic potential and ecological roles of many indigenous microbial species, cultivated or not.