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PubMed2003

The evolving face of human immunodeficiency virus-related progressive multifocal leukoencephalopathy: defining a consensus terminology.

There is a need for consistent definition of human immunodeficiency virus (HIV)-associated cases of progressive multifocal leukoencephalopathy (PML), especially following the profound disease changes that have resulted from the use of highly active antiretroviral therapy (HAART). According to the criteria used for diagnosis, PML cases should be either referred to as "histology-confirmed," with evidence of JC virus (JCV) infection in brain, "laboratory-confirmed," with detection of JCV DNA in cerebrospinal fluid (CSF), or "possible," in the presence of typical clinical and radiological picture, but no demonstration of JCV infection. Disease outcome should be defined by the evidence or lack of evidence of disease activity, rather than using survival or other variables. Disease activity should be based on clinical (scored neurological examination), radiological (magnetic resonance imaging), and virological (JCV DNA levels in CSF) indicators, to be assessed regularly, e.g., every 3 months until evidence of disease arrest or death. Furthermore, parallel assessments of other HIV-associated manifestations, including CD4+ cell counts and viral load, are required. A standard patient classification would be helpful for clinical management of PML patients, for their inclusion in clinical studies, and also will increase our current knowledge of PML and its evolution in relation with HAART.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Dislocation dynamics in an anisotropic stripe pattern.

The dynamics of dislocations confined to grain boundaries in a striped system are studied using electroconvection in the nematic liquid crystal N4. In electroconvection, a striped pattern of convection rolls forms for sufficiently high driving voltages. We consider the case of a rapid change in the voltage that takes the system from a uniform state to a state consisting of striped domains with two different wave vectors. The domains are separated by domain walls along one axis and a grain boundary of dislocations in the perpendicular direction. The pattern evolves through dislocation motion parallel to the domain walls. We report on features of the dislocation dynamics. The kinetics of the domain motion is quantified using three measures: dislocation density, average domain wall length, and total domain wall length per area. All three quantities exhibit behavior consistent with power-law evolution in time, with the defect density decaying as t(-1/3), the average domain wall length growing as t(1/3), and the total domain wall length decaying as t(-1/5). The two different exponents are indicative of the anisotropic growth of domains in the system.

Journal Article↗
PubMed1990

[The prognostic factors and evolution of the quality of life in primary biliary cirrhosis].

The prognostic factors and the evolution of the quality of life were evaluated in 38 patients with primary biliary cirrhosis (94.7% females, mean age 52.6 +/- 2.0 years) followed up for more than 36 months (mean 65.3 +/- 3.7 months). Karnofsky's index significantly declined during follow up (p less than 0.05) in a parallel fashion to modified Child's hepatic functional class (p less than 0.05) and to the days of hospital readmission (p less than 0.05). Eleven patients (28.9%) died, and the median survival was 88.7 months. The comparison of the actuarial curves showed the following to be significant poor prognostic factors at the time of diagnosis: a) clinical: more than one associated autoimmune disease, weight loss of more than 10% of the ideal weight, jaundice, upper gastrointestinal hemorrhage associated with portal hypertension, portal-systemic encephalopathy and a modified Child's hepatic functional class of 9 or more; b) biochemical: serum albumin lower than 3.5 g/dl and bilirubin higher than 2 mg/dl; c) histological: Total histological activity index of 10 or more and erosive necrosis index of 2 or more (Knodell et al.), lobular granulomas, and stage IV (Ludwig et al). A significant correlation was found (p less than 0.001) between the R index of the Mayo Clinic and the mean survival time of our patients. As a temporary policy, we indicate hepatic transplant when R is 9.2 or higher (life expectancy lower than 24 months), awaiting our own probabilistic prognostic model with the inclusion of quality of life criteria.

Adult↗
PubMed1992

Evidence for insulin dependent hepatic microsomal gamma-linolenic acid chain elongation in spontaneously diabetic Wistar BB rats.

We studied hepatic microsomal gamma-linolenoyl-CoA elongation and fatty acid composition of liver microsomes in spontaneously diabetic Wistar BB rats. The liver microsomal gamma-linolenoyl-CoA elongation was decreased in diabetic Wistar BB rats during both normo- and hyperglycemic periods and restored during the hypoglycemic period following insulin treatment. These results are in agreement with our previously reported data on linoleic acid delta 6 and delta 5 desaturations and support the non-parallel relationship between the chain elongation system and the glycemia. The fatty acid composition of BB rat liver microsomes was only partially consistent with the gamma-linolenoyl-CoA elongation activity at the different periods of glycemia, probably because factors other than elongation impairments were involved in the evolution of fatty acid composition.

Acyl Coenzyme A↗
PubMed2004

Effect of anesthesia on the signal intensity in tumors using BOLD-MRI: comparison with flow measurements by Laser Doppler flowmetry and oxygen measurements by luminescence-based probes.

BOLD-contrast functional magnetic resonance imaging (MRI) was used to assess the evolution of tumor oxygenation and blood flow after administration of four different anesthetics: pentobarbital (60 mg/kg), ketamine/xylazine (80/8 mg/kg), fentanyl/droperidol (0.078/3.9 mg/kg), and isoflurane (1.5%). Gradient echo sequences were carried out at 4.7 Tesla in a TLT tumor model implanted in the muscle of NMRI mice. In parallel experiments, tumor blood flow and tumor pO2 were measured using the OxyLite/OxyFlo probe system. A comparison was made with the changes occurring in the skeletal muscle (host tissue). The signal intensity was dramatically decreased in tumors after administration of anesthetics, except isoflurane. These results correlated well with measurements of oxygenation and blood perfusion. Isoflurane produced constant muscle pO2 and blood perfusion although large transient fluctuations in pO2 and blood flow were reported in some tumors. Our results emphasize the need for careful monitoring of the effects of anesthesia when trying to identify new therapeutic approaches that are aimed at modulating tumor hemodynamics.

Anesthetics↗
PubMed1989

Evidence that the two free sulfhydryl groups of plasma fibronectin are in different local environments. Saturation-recovery electron spin resonance study.

Human plasma fibronectin is a dimer consisting of two subunits; each contains two cryptic thiol groups that were selectively labeled with an 15N,2H-maleimide spin label. Previous studies using conventional X-band electron spin resonance (ESR) methods showed that the spectrum of the labeled protein displays a single strongly immobilized component with an effective rotational correlation time of approximately 17 ns, suggesting that the physical environments of the two labeled sites per chain are indistinguishable. Here we have used saturation-recovery ESR to measure directly electron spin-lattice relaxation time (T1) of the labeled protein in solution at 27 degrees C. Interestingly, the time evolution of the signal was found to be biphasic, which was deconvoluted into two T1 values of 1.37 and 4.53 microseconds. Thus, the two spin-labeled sulfhydryl sites of plasma fibronectin (Fn), being similar in rates of rotational diffusion, differ by a factor of 3.2 in T1. Parallel experiments using various fibronectin fragments showed that the 1.37-microseconds component is associated with the label attached onto the thiol located in between the DNA-binding and the cell-binding domains, and the 4.53-microseconds component is associated with the label attached onto the thiol located within the carboxyl-terminal fibrin-binding domain. The data suggest that the saturation-recovery ESR is a useful method for differentiating multiple spin-labeled sites on macromolecules in which the labels undergo similar rates of rotational motion.

Electron Spin Resonance Spectroscopy↗
PubMed2004

Collective behaviour in two-dimensional cobalt nanoparticle assemblies observed by magnetic force microscopy.

The use of magnetic nanoparticles in the development of ultra-high-density recording media is the subject of intense research. Much of the attention of this research is devoted to the stability of magnetic moments, often neglecting the influence of dipolar interactions. Here, we explore the magnetic microstructure of different assemblies of monodisperse cobalt single-domain nanoparticles by magnetic force microscopy and magnetometric measurements. We observe that when the density of particles per unit area is higher than a determined threshold, the two-dimensional self-assemblies behave as a continuous ferromagnetic thin film. Correlated areas (similar to domains) of parallel magnetization roughly ten particles in diameter appear. As this magnetic percolation is mediated by dipolar interactions, the magnetic microstructure, its distribution and stability, is strongly dependent on the topological distribution of the dipoles. Thus, the magnetic structures of three-dimensional assemblies are magnetically soft, and an evolution of the magnetic microstructure is observed with consecutive scans of the microscope tip.

Anisotropy↗
PubMed2000

Two PKR inhibitor HCV proteins correlate with early but not sustained response to interferon.

BACKGROUND & AIMS: The NS5A and the E2 proteins of hepatitis C virus (HCV)-1b can bind and inhibit in vitro the interferon (IFN)-induced cellular kinase PKR. The role of such interaction in modulating the antiviral effect of IFN is still controversial. We have analyzed the E2 and the NS5A sequences in HCV-1b-infected patients treated with IFN to assess whether and how different combinations of wild-type and mutant proteins correlated with early and long-term virological response. METHODS: In 30 patients, sequences of pretreatment and on-treatment E2-PePHD and NS5A-PKR binding domain (including the putative ISDR) were analyzed in parallel by sequencing cDNA-polymerase chain reaction products and up to 25 independent clones. RESULTS: The E2-PePHD sequence was highly conserved with a homogeneous quasispecies and was identical in 29 of 30 cases with no association with the pattern of response and no evidence of evolution during therapy. Patients with a mutated NS5A-ISDR had a higher rate of early virological response (67%) than cases with wild-type ISDR (17%). This association was lost in long-term responders (33% vs. 17%). CONCLUSIONS: Although the highly conserved E2-PePHD motif might contribute to reduce IFN responsiveness, variations within this region do not seem to play a role in modulating IFN sensitivity. The NS5A-ISDR sequence influenced the early, but not the sustained response, to IFN, suggesting that other factors may be more important for the long-term outcome of therapy.

Adult↗
PubMed1987

Evidence for high peptide alpha-amidating activity in the pancrease from neonatal rats.

A high peptidylglycine alpha-amidating mono-oxygenase (PAMase) activity has been measured in the pancreas of neonatal rats. A significant fraction of this activity is contained in the beta cells of the islets of Langerhans and is colocalized with thyrotropin-releasing hormone (TRH) and its precursor in secretory granules. The ontogenetic variation of PAMase activity in the pancrease parallels that of TRH concentrations, suggesting that this enzymatic activity is directly related to TRH biosynthesis. In addition, PAMase activity is able to generate TRH when incubated with less than Glu-His-Pro-Gly, a tetrapeptide present as a repetitive sequence in the TRH precursor. The perinatal evolution of the TRH precursor levels in the pancreas is similar to that of PAMase activity (unpublished results). Thus, the neonatal rat pancreas offers an endocrine model in which the levels of a neuropeptide precursor and an enzyme activity, involved in the posttranslational modification of this precursor, are similarly regulated. Our results suggest also that a fraction of PAMase activity may be produced outside of the beta cells and related to the biosynthesis of COOH-terminally amidated peptide(s) other than TRH. The ontogenetic changes in PAMase activity imply that the synthesis of this peptide(s) is high during the neonatal period, decreasing thereafter.

Aging↗
PubMed1998

Genetic and morphological analyses reveal a critical interaction between the C-termini of two SNARE proteins and a parallel four helical arrangement for the exocytic SNARE complex.

In a screen for suppressors of a temperature-sensitive mutation in the yeast SNAP-25 homolog, Sec9, we have identified a gain-of-function mutation in the yeast synaptobrevin homolog, Snc2. The genetic properties of this suppression point to a specific interaction between the C-termini of Sec9 and Snc2 within the SNARE complex. Biochemical analysis of interactions between the wild-type and mutant proteins confirms this prediction, demonstrating specific effects of these mutations on interactions between the SNAREs. The location of the mutations suggests that the C-terminal H2 helical domain of Sec9 is likely to be aligned in parallel with Snc2 in the SNARE complex. To test this prediction, we examined the structure of the yeast exocytic SNARE complex by deep-etch electron microscopy. Like the neuronal SNARE complex, it is a rod approximately 14 nm long. Using epitope tags, antibodies and maltose-binding protein markers, we find that the helical domains of Sso, Snc and both halves of Sec9 are all aligned in parallel within the SNARE complex, suggesting that the yeast exocytic SNARE complex consists of a parallel four helix bundle. Finally, we find a similar arrangement for SNAP-25 in the neuronal SNARE complex. This provides strong evidence that the exocytic SNARE complex is a highly conserved structure composed of four parallel helical domains whose C-termini must converge in order to bring about membrane fusion.

Amino Acid Sequence↗
PubMed2005

Unparallel diversification in bacterial microcosms.

Adaptive speciation has gained popularity as a fundamental process underlying the generation of diversity. We tested whether populations respond to similar forms of disruptive selection by diversifying in similar or parallel ways by investigating diversified populations of Escherichia coli B evolved in glucose and glucose-acetate environments. In both environments, the populations have differentiated into two phenotypes, named for their characteristic colony morphologies: large (L) and small (S). Each type is heritable and this polymorphism (or 'diversified pair') appears to be maintained by negative frequency dependence. The L and S phenotypes from different environments are convergent in their colony morphology and growth characteristics. We tested whether diversification was parallel by conducting competition experiments between L and S types from different environments. Our results indicate that replicate diversified pairs from different environments have not diversified in parallel ways and suggest that subtle differences in evolutionary environment can crucially affect the outcome of adaptive diversification.

Acetates↗
PubMed2001

Reversible shape evolution of Ge islands on Si(001).

The evolution of strained Ge/Si(001) islands during exposure to a Si flux was investigated by scanning tunneling microscopy. Dome islands display appreciable shape changes at Si coverages as low as 0.5 monolayer. With increasing coverage, they transform into [105]-faceted pyramids, and eventually into stepped mounds with steps parallel to the <110> directions. These morphological changes are induced by alloying and represent a complete reversal of those previously observed during Ge island growth. The results are interpreted with a simple model in which the equilibrium shape of an island mainly depends on its volume and composition.

Journal Article↗
PubMed2026

To Treat or Not to Treat: Navigating Early-Stage CLL in the Era of Targeted Therapy.

Chronic lymphocytic leukemia (CLL) is most frequently diagnosed at early, asymptomatic stages (Rai 0/Binet A), in which a watch-and-wait strategy remains the standard of care, based on historical trials demonstrating no overall survival benefit from early treatment. Over the past two decades, however, substantial advances in genomic profiling-including immunoglobulin heavy-chain variable region (IGHV) mutational status, TP53 disruption, recurrent gene mutations, and complex karyotype-have uncovered marked biological heterogeneity among early-stage patients and substantially improved prediction of disease progression. In parallel, targeted therapies such as Bruton tyrosine kinase (BTK) inhibitors and venetoclax-based combinations have transformed the management of symptomatic CLL, raising renewed interest in whether early intervention might favorably alter the natural history of biologically high-risk disease. In this review, we critically examine the evolution of prognostication in early-stage CLL, integrate contemporary molecular and clinical risk models, and summarize evidence from both historical chemotherapy-era studies and modern early-intervention trials. We discuss key unresolved controversies, including reliance on surrogate endpoints, the risks of overtreatment, and the persistent absence of an overall survival benefit across all early-treatment strategies. Finally, we outline future research priorities, including refined genomic stratification, minimal residual disease-driven (MRD)-driven approaches, and combination targeted therapies currently under investigation. Despite renewed interest in preemptive treatment, available evidence supports continued observation for asymptomatic patients outside clinical trials.

Humans↗
PubMed1980

[Serum lipase assay for clinical use. Critical study (author's transl)].

An accurate, quick, and reproducible method to assay serum lipase activity allowed a parallel study of lipase and amylase in 147 patients. Lipase appeared very specific of pancreatic distress. In acute pancreatitis its increase was constant, frank, quick and lasting. It brought a diagnostic argument superior to the dosages of amylase activities in serum and/or urine. But its value as an evolutive and pronostic test was as much limited. Its interest as a negative argument for differential diagnosis was not superior either. In chronic pancreatic diseases, it gave evidence of massive spread or complications.

Abdomen, Acute↗
PubMedDate not supplied

A method for the study of the dynamics of atherosclerotic involvement of human coronary arteries.

A method able to reveal the progression of atherosclerosis from children to mature adults is proposed, based on the successive light microscopic examination of similar selected topographic sites of the coronary arterial tree placed in sequence according to age, sex and branching anatomical pattern. The dynamic reconstruction of thousands of static views revealed a linear and parallel increase in the number of all types of early atherosclerotic lesions: fibromuscular plaques, intimal necrotic areas, incorporated microthrombi and fatty streaks. Some endogenous and exogeneous risk factors for coronary heart disease accelerated this age-related rate of progression and also gave rise to particular cycles of evolution toward lesions of possible clinical significance.

Adolescent↗
PubMed2002

Rapid evolution of escape ability in Trinidadian guppies (Poecilia reticulata).

Predators are widely assumed to create selection that shapes the evolution of prey escape abilities. However, this assumption is difficult to test directly due to the challenge of recording both predation and its evolutionary consequences in the wild. We examined these events by studying natural and experimental populations of Trinidadian guppies, Poecilia reticulata, which occur in distinct high-predation and low-predation environments within streams. Importantly, in the last two decades several populations of guppies have been experimentally introduced from one type of predatory environment into the other, allowing measurements of the consequences of change. We used this system to test two hypotheses: First, that changes in predatory environments create phenotypic selection favoring changes in escape ability of guppies, and second, that this selection can result in rapid evolution. For the first test we compared escape ability of wild caught guppies from high- versus low-predation environments by measuring survival rates during staged encounters with a major predator, the pike cichlid Crenicichla alta. We used guppies from three streams, comparing two within-stream pairs of natural populations and three within-stream pairs of an introduced population versus its natural source population. In every comparison, guppies from the high-predation population showed higher survival. These multiple, parallel divergences in guppy survival phenotype suggest that predatory environment does create selection of escape ability. We tested our second hypothesis by rearing guppies in common garden conditions in the laboratory, then repeating the earlier experiments using the F2 generation. As before, each comparison resulted in higher survival of guppies descended from the high-predation populations, demonstrating that population differences in escape ability have a genetic basis. These results also show that escape ability can evolve very rapidly in nature, that is, within 26-36 generations in the introduced populations. Interestingly, we found rapid evolutionary loss of escape ability in populations introduced into low-predation environments, suggesting that steep fitness trade-offs may influence the evolution of escape traits.

Animals↗
PubMed1999

Physical mapping of ribosomal RNA genes in peonies (Paeonia, Paeoniaceae) by fluorescent in situ hybridization: implications for phylogeny and concerted evolution.

Physical maps of the 18S-5.8S-26S ribosomal RNA genes (rDNA) were generated by fluorescent in situ hybridization for five diploid Paeonia species, P. delavayi and P. rockii of section Moutan, and P. emodi, P. tenuifolia, and P. veitchii of section Paeonia. Of five pairs of mitotic chromosomes, rDNA loci were mapped near the telomeres of chromosomes 3, 4, and 5 of P. rockii and P. tenuifolia, chromosomes 2, 3, 4, and 5 of P. delavayi, and all five pairs of chromosomes of P. emodi and P. veitchii. Combining this information with the previously obtained rDNA maps of P. brownii and P. californica of section Oneapia, we hypothesized that the most recent common ancestor of extant peony species had three rDNA loci located on chromosomes 3, 4, and 5. Increase in number of rDNA loci occurred later in each of the three sections, and the increase from three to four loci represents a parallel gain of an rDNA locus on chromosome 2 in P. delavayi of section Moutan and P. brownii of section Oneapia. The increase in number of rDNA loci likely resulted from the translocation of rDNA repeats from chromosomes bearing rDNA loci to chromosomes without them; such translocation is probably facilitated by the telomeric location of rDNA loci. For allotetraploid peony species lacking polymorphism in sequences of the internal transcribed spacers (ITS) of rDNA, the rDNAs derived from divergent diploid parents may have been homogenized through concerted evolution among at least six rDNA loci in the allotetraploids. Chromosomal location of rDNA loci has a more substantial impact on the tempo of concerted evolution than the number of loci.

Journal Article↗