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Treatment of Cushing's disease by transsphenoidal, pituitary microsurgery: prognosis factors and long-term follow-up.

Transsphenoidal pituitary microsurgery is considered as the best treatment of Cushing's disease. However, some recent studies reported disappointing results, leading their authors to suggest the possibility of returning to a first line adrenalectomy treatment. The aim of this study was to evaluate long-term results of transsphenoidal surgery in Cushing's disease, with special interest in factors that could affect the surgical outcome on the one hand and particular attention to surgical endocrine effects on the other. Fifty consecutive patients (34 females, 16 males, mean age 29.64 +/- 1.52 yr) were studied. The median post-operative follow-up was 71.5 months (range 25-219). Clinical, biological, surgical and pathological data between the success and failure groups were compared. Criteria of cure were: normal urinary free cortisol excretion, circadian cortisol rhythm and low dose dexamethasone test. Recovery of corticotroph and somatotroph functions were followed using the insulin test. Particular attention is given to clinical evolution in evaluating other pituitary functions. T4 or FT4, prolactin, E2 in women, testosterone in men, were measured. TRH and LHRH tests were not systematically performed. Only two parameters differed significantly between the cured and failure groups: the size of the adenomas was smaller and the pathological confirmation of the adenoma more frequent in the cured group. One patient had permanent corticotropic failure while two other had impaired response to hypoglycemia with normal cortisol basal levels. No acquired hypothyroidism nor hypogonadism were observed except in a patient who underwent two operations and radiotherapy. Recovery of GH function was slow. Definitive short stature was observed in all the patients whose disease began before the age of 16. Two patients had permanent diabetes insipidus. In conclusion, the most favorable prognosis in transsphenoidal surgery for Cushing's disease is observed in case of microadenoma confirmed by pathological examination. With this treatment, we obtained satisfactory results in Cushing's disease with minimal complications and no necessity of life-long endocrine substitutive therapy.

Adenoma↗

Hydrophobic hydrophilic phenomena in biochemical processes.

The evolution of concepts developed in the study of the hydrophobic affect is surveyed, within the more general context of solvent-induced effects. A systematic analysis of the solvent-induced contribution to the driving force for the process of protein folding has led to two important modifications in our understanding of these effects. First, the conventional concepts of hydrophobic solvation and hydrophobic interactions had to be replaced by their respective conditional effects. Second, each of the hydrophobic effects has also a corresponding hydrophilic counterpart. Some of the latter effects could contribute significantly to the total driving force for the process of protein folding, and perhaps even dominate the driving force for biochemical processes.

Biochemical Phenomena↗

Studies of tip wear processes in tapping mode atomic force microscopy.

Tip integrity is crucial to atomic force microscope image quality. Tip wear not only compromises image resolution but also introduces artifacts. However, the factors that govern wearing have not been systematically studied. The results presented here of tip wearing on a rough titanium surface were determined by monitoring changes in tip shape and the evolution of histograms of complex surface curvatures under different control parameters. In contrast with the common assumption that operating at a low set point (the ratio of tapping amplitude to free oscillation amplitude) wears the tip quickly, we observed that a low set point actually minimizes tip wear on a hard surface regardless of the free amplitude. The results can be interpreted qualitatively with theoretical calculations based on momentum exchange at tapping impact. Operating at a low set point allows more robust scanning than with a high set point (tapping near free amplitude), providing a method to slow down tip wear. Another advantage of a low set point is that amplitude error grows faster than with a high set point by nearly an order of magnitude, permitting an increase in scanning speed.

Journal Article↗

New nuclear evidence for the oldest divergence among neognath birds: the phylogenetic utility of ZENK (i).

To date, there is little consensus concerning the phylogenetic relationships among neognath orders, which include all extant birds except ratites and tinamous. Different data sets, both molecular and morphologic, have yielded radically different and often unresolved ordinal topologies, especially within the neoaves clade. This lack of resolution and ongoing conflict indicates a need for additional phylogenetic characters to be applied to the question of higher-level avian phylogeny. In this study, sequences of a single-copy nuclear gene, ZENK, were used to reconstruct an ordinal-level phylogeny of neognath birds. Strong support was indicated for the oldest divergence within Neognathae; the chicken- and duck-like birds formed a clade that was sister to all other modern birds. In addition, many families of traditional taxonomic orders clustered together in the ZENK tree, indicating the gene's general phylogenetic reliability. However, within the neoaves clade, there was little support for relationships among orders, which is a result similar to all other recent molecular studies of higher-level avian phylogeny. This similarity among studies suggests the possibility of a rapid radiation of the major neoaves lineages. Despite the ongoing lack of neoaves resolution, ZENK's sequence divergence and base composition patterns indicate its general utility as a new phylogenetic marker for higher-level avian systematics.

3' Untranslated Regions↗

FixJ-regulated genes evolved through promoter duplication in Sinorhizobium meliloti.

The FixLJ two-component system of Sinorhizobium meliloti is a global regulator, turning on nitrogen-fixation genes in microaerobiosis. Up to now, nifA and fixK were the only genes known to be directly regulated by FixJ. We used a genomic SELEX approach in order to isolate new FixJ targets in the genome. This led to the identification of 22 FixJ binding sites, including the known sites in the fixK1 and fixK2 promoters. FixJ binding sites are unevenly distributed among the three replicons constituting the S. meliloti genome: a majority are carried either by pSymA or by a short chromosomal region of non-chromosomal origin. Thus FixJ binding sites appear to be preferentially associated with the pSymA replicon, which carries the fixJ gene. Functional analysis of FixJ targets led to the discovery of two new FixJ-regulated genes, smc03253 and proB2. This FixJ-dependent regulation appears to be mediated by a duplication of the whole fixK promoter region, including the beginning of the fixK gene. Similar duplications were previously reported for the nifH promoter. By systematic comparison of all promoter regions we found 17 such duplications throughout the genome, indicating that promoter duplication is a common mechanism for the evolution of regulatory pathways in S. meliloti.

Amino Acid Sequence↗

Introducing small-world network effects to critical dynamics.

We analytically investigate the kinetic Gaussian model and the one-dimensional kinetic Ising model of two typical small-world networks (SWN), the adding type and the rewiring type. The general approaches and some basic equations are systematically formulated. The rigorous investigation of the Glauber-type kinetic Gaussian model shows the mean-field-like global influence on the dynamic evolution of the individual spins. Accordingly a simplified method is presented and tested, which is believed to be a good choice for the mean-field transition widely (in fact, without exception so far) observed for SWN. It yields the evolving equation of the Kawasaki-type Gaussian model. In the one-dimensional Ising model, the p dependence of the critical point is analytically obtained and the nonexistence of such a threshold p(c), for a finite-temperature transition, is confirmed. The static critical exponents gamma and beta are in accordance with the results of the recent Monte Carlo simulations, and also with the mean-field critical behavior of the system. We also prove that the SWN effect does not change the dynamic critical exponent z=2 for this model. The observed influence of the long-range randomness on the critical point indicates two obviously different hidden mechanisms.

Journal Article↗

Numerical study of miscible fingering in a time-dependent gap Hele-Shaw cell.

We perform a detailed numerical study of the evolution of a miscible fluid droplet in a time-dependent gap Hele-Shaw cell. The development of the emerging fingering instabilities is systematically analyzed by intensive and highly accurate numerical simulations. We focus on the influence of three relevant physical parameters on the interface dynamics: the Pélclet number Pe, the viscosity contrast A, and the Korteweg stress parameter delta. Consistently with conventional miscible Saffman-Taylor studies in constant-gap Hele-Shaw cells, our results demonstrate that more vigorous fingering is observed at higher Pe and larger A. Concerning the specific role of Pe and A, we deduce two general results: higher Péclet number favors branching around a nearly circular region (which leads to longer interfacial lengths); while larger viscosity contrast results in more significant finger penetrations (which is quantitatively expressed by larger diameter of gyration). We have also verified that the Korteweg stress parameter delta does act as an effective interfacial tension: it stabilizes the miscible interface, leading to fingering patterns that present a greater resemblance with the structures obtained in similar immiscible situations. Finally, we have identified the development of a visually striking phenomenon in the limit of high Pe, large A , and relatively small delta: some outward fingers pinch, and subsequent droplet detachment is observed. We show that such a droplet detachment process can be prevented by the action of stronger interfacial stresses. This last finding provides additional evidence for the claim that the Korteweg stresses can be treated as an ersatz interfacial tension in diffusing fluids.

Journal Article↗

On hidden heterogeneity in directional asymmetry--can systematic bias be avoided?

Directional asymmetry (DA) biases the analysis of fluctuating asymmetry (FA) mainly because among-individual differences in the predisposition for DA are difficult to detect. However, we argue that systematic bias mainly results from predictable associations between signed right-left asymmetry and other factors, i.e. from systematic variation in DA. We here demonstrate methods to test and correct for this, by analysing bilateral asymmetry in size and shape of an irregular sea urchin. Notably, in this model system, DA depended significantly on body length and geographic origin, although mean signed asymmetry (mean DA) was not significant in the sample as a whole. In contrast to the systematic variation in DA, undetectable, random variability in the underlying DA mainly leads to reduced statistical power. Using computer simulations, we show that this loss of power is probably slight in most circumstances. We recommend future studies on FA to routinely test and correct for not only as yet for mean DA, but also for systematic variation in DA.

Analysis of Variance↗

The changing morphology and increasing deceleration of supernova 1993J in M81

Twenty consecutive Very Long Baseline Interferometry images of supernova 1993J from the time of explosion to the present show the dynamic evolution of the expanding radio shell of an exploded star. High-precision astrometry reveals that the supernova expands isotropically from its explosion center. Systematic changes in the images may reflect a pattern of anisotropies and inhomogeneities in the material left over from the progenitor star. As the shock front sweeps up the material in the surrounding medium, it is increasingly decelerated and influenced by the material. After 5 years, the supernova has slowed to half of its original expansion velocity and may have entered the early stages of the adiabatic phase common in much older supernova remnants in the Milky Way Galaxy.

Journal Article↗

Better information for better health care: the Evidence-based Practice Center program and the Agency for Healthcare Research and Quality.

To provide decision makers with the best available evidence, the Agency for Healthcare Research and Quality established a network of Evidence-based Practice Centers across North America. The centers perform systematic reviews on important questions posed by partner organizations about clinical, organizational, and policy interventions in healthcare. The Agency works closely with partners and other decision maker s to help translate that evidence into practice or policy. In this paper, we review important lessons we have learned over the past 7 years about how to increase the efficiency and impact of systematic reviews. Lessons concern selecting the right topics and scope, working effectively with partners, and balancing consistency and flexibility in methods. We examine continuing evolutions of the program and the impact of planned work on comparative effectiveness performed as part of the Medicare Modernization Act of 2003.

Evidence-Based Medicine↗

Did God create our universe? Theological reflections on the Big Bang, inflation, and quantum cosmologies.

The sciences and the humanities, including theology, form an epistemic hierarchy that ensures both constraint and irreducibility. At the same time, theological methodology is analogous to scientific methodology, though with several important differences. This model of interaction between science and theology can be seen illustrated in a consideration of the relation between contemporary cosmology (Big Bang cosmology, cosmic inflation, and quantum cosmology) and Christian systematic and natural theology. In light of developments in cosmology, the question of origins has become theologically less interesting than that of the cosmic evolution of a contingent universe.

Extraterrestrial Environment↗

[Blood as a clinical sign in the corpus hippocraticum].

Blood as a clinical sign has a key role throughout the Corpus Hippocraticum: as the most prominent and visible of the four fluids which make up the humoral system, it recurs quite often as a crucial cue for prognosis. This paper collects and classifies some of the most important loci in the Corpus which are devoted to describe and interpret the different qualities of human blood and the ways it can be altered and corrupted; this recollection clearly shows the systematic character of the Hippocratic treatment of blood and its function within the whole theoretical building of CH. The status of blood within the evolution of medical theories in the Antiquity is also scrutinized, especially as far as the polemics on encephalocentrism vs haemocentrism is concerned. The nature of observations about the manifestation of pure and altered blood sheds light on the epistemological status of clinical observation within the clinical methods of the Hippocratic school.

Blood Physiological Phenomena↗

[Study of polymorphism in human rRNA gene clusters. Population and familial analysis of basic types of RFLP].

The frequency and average amount of copy number per genome were defined for standard and a number of new variants of BamHI 5'-NTS RFLP from populations of Moscow, Riga and individuals with Down syndrome. It was demonstrated that the populations studied differ neither in population frequency nor in the average amount of copy number of the variants. New variants were detected in the EcoRI 3'-NTS RFLP system and their amplification, as well as discordance among MZ twins. Possible target for methylation in the HindII site of 3' end of 28S rRNA gene was revealed. Analysis of data obtained demonstrated inefficiency of using the RFLP systems in systematic mapping of NOR-chromosomes. Our data also suggested a possible role of amplification of one copy repeated unit rRNA genes in their evolution.

Down Syndrome↗

[Pharmacy in the 90's: the modern process of drug registration].

The 5 phases of the development of a drug are reviewed in the light of the modern scientific guide-lines. The needed documentation (master-file) and technical-scientific data are (and will be) constantly more demanding. Therefore, the drugs will undergo a hard selection. The Regulations for Marketing Authorizations, already of a high regulatory level, are increasingly in agreement. Therefore, the gap existing in the past among countries with a different technological evolution is filled. The measures of the Health Authorities before and after the authorization to the marketing of the medicinal specialties are always more systematic. Many procedures clearly pointing out the process of the study of a substances destined to become a drug (GMP - GLP - GCP - DMF) are now established on an international level. The drugs of the nineties will undergo a very hard selection, to warrant a positive risk-benefit balance and a profitable cost-benefit ratio. The compound under study are numbered in hundreds, whereas those which pass the screening and can be used as specialties are very few. The costs of development can be estimated in tens of billion liras and the times required on average are of about 10 years for each project. The attention of the scientists and the pharmaceutical companies is directed especially to the development of innovative drugs for the treatment of the most important diseases.

Drug Design↗

[Paraneoplastic syndromes in cancer of the kidney (author's transl)].

Starting with the description of their own observations of paraneoplastic syndromes in adult patients with cancer of the kidneys, the authors discuss the possible pathogenetic mechanisms and the more characteristic clinical features of said syndrome. They conclude by advocating a systematic search for such paraneoplastic syndromes as an aid to early diagnosis of renal malignancy and also as a working parameter for assessing the evolution of the tumor and the effectiveness of treatment.

Amyloidosis↗

Unraveling cellular dynamic changes in tumor evolution induced by long-term low dose-rate radiation.

BACKGROUND: In recent years, there has been a steady increase in professionals engaged in radioactive work. The biological impacts of long-term exposure to low dose-rate radiation remain elusive, as there is a dearth of systematic research in this field. METHODS: BEAS-2B cells were used to establish a cell model with continuous passaging after radiation exposure, which was subsequently subjected to in vivo tumorigenesis assays and in vitro malignant phenotype experiments. By scRNA-seq, we conducted copy number variation analysis, cell trajectory analysis, and cell communication analysis. Furthermore, we used FACS, molecular docking, multiplex immunohistochemistry, qRT-PCR, and co-immunoprecipitation to validate and further explore the molecular mechanisms driving tumor evolution. RESULTS: Long-term low dose-rate exposure is associated with a higher degree of malignancy, as evidenced by the induction of more CNV and EMT events, as well as the delayed activation of DNA repair pathways, which trigger increased genomic instability. The long-term low dose-rate specific ligand-receptor pair, ANGPTL4-SDC4, enhances cell malignancy by promoting angiogenesis in newly formed lung tumor cells. CONCLUSIONS: This study not only provides the first evidence and mechanistic explanation that long-term low dose-rate radiation leads to increased cellular malignancy but also offers valuable theoretical insights into the dynamic processes of early tumor evolution in lung cancer within the realm of tumor biology.

Humans↗