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PubMed2002

Early-stage idiopathic (primary) myelofibrosis--current issues of diagnostic features.

Idiopathic myelofibrosis (IMF) is generally characterized by bone marrow (BM) fibrosis, anemia, splenomegaly and a leuko-erythroblastic blood picture. Although, histopathology is in keeping with the assumption of a stepwise evolution of the disease, little hematological data are available for patients with prefibrotic and early stages of disease. Therefore a clinicopathological study was performed that included firstly an exploratory sample of 68 patients with minor supportive therapy in whom BM biopsies during follow-up (41 +/- 32 months) revealed an evolution of a prefibrotic or very early fibrotic lesion into overt IMF. The validation sample consisted of 556 patients with pretreatment marrow specimens on admission. Diagnostic features and BM lesions were identical compared with the patients of the exploratory sample at their first examination. BM biopsies were processed by routine stainings including silver impregnation (reticulin fibers) and frequently also by immunohistochemistry to identify megakaryocytes and erythroid precursor cells more properly. Apart from minor hemorrhage and peripheral thrombosis patients with early stage IMF presented with non-specific symptoms including varying degrees of leukocytosis (51%), anemia (38%), a platelet count exceeding 600 x 10(9)/l (86%), splenomegaly (15%) and increase in leukocyte alkaline phosphatase (LAP) (24%) and serum lactate dehydrogenase (LDH) (20%). BM histology confirmed a moderate increase in hematopoiesis with a mixed granulocytic and megakaryocytic myeloproliferation, a reduction of erythroid precursors and significant megakaryocytic abnormalities. In keeping with the first BM examination of the exploratory sample no or only a borderline to slight increase in reticulin fibers was detectable, however, in 68 of 134 patients follow-up biopsies revealed a transition into overt IMF (intervals about three years). Median survival of this cohort with early-stage IMF was 129 months thus contrasting manifest IMF with an usually more unfavorable prognosis. Recognition of early stage IMF certainly alters the generally applied diagnostic criteria of this disorder. Regarding patients with associated thrombocytosis, differentiation from essential thrombocythemia is recommended. Moreover, characterization of early stage IMF probably exerts an impact on survival and may influence the decision to perform a BM transplantation.

Adult↗
PubMed2003

Time-dependent random walks and the theory of complex adaptive systems.

Motivated by novel results in the theory of complex adaptive systems, we analyze the dynamics of random walks in which the jumping probabilities are time dependent. We determine the survival probability in the presence of an absorbing boundary. For an unbiased walk, the survival probability is maximized in the case of large temporal oscillations in the jumping probabilities. On the other hand, a random walker who is drifted towards the absorbing boundary performs best with a constant jumping probability. We use the results to reveal the underlying dynamics responsible for the phenomenon of self-segregation and clustering observed in the evolutionary minority game.

Adaptation, Biological↗
PubMed2002

Liver transplantation and hepatitis C.

End-stage liver disease caused by chronic hepatitis C viral infection is one of the major indications for liver transplantation. However, evidence for ongoing viral replication can already be found days after surgery and may lead sequentially to lobular hepatitis, chronic active hepatitis, fibrosis and liver cirrhosis. In some patients, this evolution is remarkably fast, most probably enhanced by the immunosuppressive therapy. A minority of patients develop a clinical picture of progressive cholestatic liver disease with histological signs of chronic rejection, which may necessitate retransplantation. While the 1- and 5-year survival rates for all patients transplanted because of hepatitis C virus (HCV)-induced liver cirrhosis are satisfactory, severe complications of disease recurrence are nonetheless expected during the first and second decade after liver transplantation. Larger and preferably randomized studies are needed to investigate whether combination therapy with interferon and ribavirin, preferably initiated as soon as possible after liver transplantation, prevents the fast evolution to cirrhosis without the appearance of chronic rejection and the expected complications of recurrent end-stage HCV-induced liver disease. The final goal should be the inhibition of viral replication even before liver transplantation, but other antiviral strategies should probably be used to attain this goal in patients with decompensated cirrhosis. Although the recurrence of a hepatitis C infection and concomitant disease in the liver graft may cause substantial morbidity, end-stage liver disease and liver failure caused by a chronic hepatitis C infection remain good indications for liver transplantation.

Antiviral Agents↗
PubMed1993

The past as prologue.

What has the Association of American Medical Colleges (AAMC) accomplished in the last 25 years in its efforts to advance medical education, biomedical research, and health delivery in this country? Can the AAMC's past accomplishments help predict how it will respond to future challenges? To answer these questions, the author traces in detail the recent history of the AAMC, focusing on the expansion of the association's role and constituencies and how these and other changes were precipitated by recommendations in the AAMC's 1965 "Coggeshall Report." He also recounts how the AAMC has responded to the pressures and needs of recent years (such as fostering an increase in the number of practicing physicians) and describes in detail the organization and functions of the AAMC's staff, with emphasis on its six divisions and the fact that many of the complex issues that confront the AAMC transcend the boundaries of governance councils and staff divisions and dictate that association policy be based on broad consensus. Looking ahead, he sees at least four important activities that the AAMC will continue to be involved with: fostering the education of more minority students; promoting health services research; finding an appropriate role in the evolution of health care reform; and addressing the need for academic medicine to be more socially responsive. The author concludes that the AAMC's highly regarded record, its organization, and its financial stability all indicate that it will do well as it tackles the issues on the horizon and others not yet in view.(ABSTRACT TRUNCATED AT 250 WORDS)

Education, Medical, Undergraduate↗
PubMed1999

Bi-penta-bi-decaradial symmetry: A review of evolutionary and developmental trends in holothuroidea (echinodermata)

Holothuroidea, comprising the sea cucumbers, is the least studied class of extant echinoderms, yet this group possesses a wealth of features of potential interest to developmental and evolutionary biologists. Holothuroids include the most morphologically derived echinoderms, including pelagic species and spheroid, plated taxa with mouth and anus adjacent at the end of a long, flexible stalk. To begin investigating this diversity of body form, we first estimated evolutionary relationships in the class Holothuroidea based on maximum parsimony analyses of 1,075 nt of the nuclear small subunit rDNA (for six species in four orders) and on 52 informative morphological characters (for the 25 extant families). Both the morphological and molecular evidence suggests almost an inversion of the prevailing higher level classification. Character-state optimizations indicated that pronounced adult bilateral symmetry evolved three times. In one group even a regain of secondary radial symmetry is found. Respiratory trees, structures unique to holothuroids, are a relatively late innovation, are ectodermally derived, and are bilaterally symmetric, supporting the possibility that the secondary gain of bilateral symmetry in holothuroids is ectodermally derived analogous to, say, the derivation of vertebrate limb dorso-ventral axis. The test of imbricating plates found in 10% of living holothuroids is apparently not homologous with that of other heavily armored echinoderms, evolving much later and at least twice. Indirectly developing larvae, auriculariae, occur in two evolutionarily disparate clades and unlike echinoids comprise a minority of clades. We suggest that this implies the parallel convergent evolution of this larval type or, more speculatively, some form of retention of developmental constraints. J. Exp. Zool. (Mol. Dev. Evol.) 285:93-103, 1999. Copyright 1999 Wiley-Liss, Inc.

Journal Article↗
PubMed1988

Spatial and temporal characteristics of circumferential flow-function relations during acute myocardial ischemia in the conscious dog.

In the anesthetized open-chest dog the ischemic area produced by coronary occlusion is surrounded by an area of nonischemic contractile dysfunction, identified as the functional border zone. To establish whether a similar functional border zone exists in the conscious animal during acute regional ischemia and to determine its spatial dimensions and temporal changes, we performed simultaneous two-dimensional echocardiography and radioactive microsphere studies in nine chronically instrumented dogs. We produced circumferential flow-function maps at 22.5-degree intervals over the full circumference of the left ventricle at the midpapillary muscle level during control conditions, 5 minutes after left circumflex occlusion, and 2.5 hours after left circumflex occlusion. After occlusion there was no change in left ventricular end-diastolic area, an increase in left ventricular end-systolic area (p less than 0.01), and a decrease in left ventricular area ejection fraction (p less than 0.01). The circumferential extent of left ventricular dysfunction was 197 +/- 11 degrees (mean +/- SEM) at 5 minutes of left circumflex occlusion, whereas the extent of subendocardial hypoperfusion was 144 +/- 6 degrees (p less than 0.0005). This produced a functional border zone measuring 54 +/- 8 degrees, or 25% of the nonischemic myocardium, which did not change over the 2.5-hour occlusion period. Despite a modest but significant decrease in wall thickening (70 +/- 6% to 43 +/- 6%; p less than 0.01) in the functional border zone, there was no difference in subendocardial blood flow between the functional border zone and the control nonischemic area. We conclude that a discrete functional border zone exists in the conscious dog during acute regional ischemia produced by circumflex coronary occlusion, which does not change during the early evolution of myocardial infarction. The functional border zone likely contributes to minor overestimation of infarct size in the early hours after myocardial infarction if extent of left ventricular dysfunction is used as an index of infarction in humans.

Animals↗
PubMed1985

Two versions of dependence: D.S.M.-III and the alcohol Dependence Syndrome.

This paper reviews the concepts of dependence on alcohol as embodied by the Alcohol Dependence Syndrome and as proposed in the Diagnostic and Statistical Manual of the American Psychiatric Association (D.S.M.-III). Evidence in support of the unidimensionality of this concept is still controversial, and the elements necessary to diagnose dependence under each of these two proposals are different. Alcohol Dependence in the D.S.M.-III has indicators of social and occupational impairment which are not part of the Alcohol Dependence Syndrome. Knowledge on the concept of dependence will advance more rapidly if researchers begin to develop comparative studies of these two models. Future work should also include studies in the general population, with women, ethnic minorities and cross-cultural research. Longitudinal research to establish the evolution of dependence both in clinical and general populations should also be developed.

Alcoholism↗
PubMed2006

Vicariance, colonisation, and fast local speciation in Asia Minor and the Balkans as revealed from the phylogeny of spined loaches (Osteichthyes; Cobitidae).

We reconstruct the phylogeny of the morphologically diagnosable subgenera Bicanestrinia, Beysehiria, and Cobitis sensu stricto of the genus Cobitis from Asia Minor and the Balkans. We used the complete cytochrome b gene of 65 specimens in order to infer their evolutionary history in this zoogeographically interesting area. Our phylogeographic analysis did not evidence the previously suggested monophyly of the Bicanestrinia subgenus but revealed five monophyletic lineages in the area: the lineages Bicanestrinia I-IV including all species of Bicanestrinia plus the lineage Cobitis s. str. The monotypic subgenus Beysehiria from Lake Beysehir in Anatolia was closely related to the syntopic population of C. turcica and nested inside the lineage Bicanestrinia III. The strictly allopatric distribution of the four lineages of Bicanestrinia suggests that vicariance has played a major role in the diversification of Bicanestrinia. All analysed species of Cobitis s. str. from Asia Minor and Balkans were closely related to Cobitis s. str. from Central Europe, the Danube basin and the Caucasus, indicating at least two colonisation events into Asia Minor and the Balkans. A third, recent colonisation event led to the presence of C. strumicae, generally restricted to the Aegean Sea drainage, in the Danube basin. Besides the evidences of vicariance and colonisation events in the phylogenetic history of the genus Cobitis in Asia Minor and the Balkans, our analysis suggested also a rapid morphological evolution of C. bilseli in a lacustrine environment. Application of Cobitis mitochondrial cytochrome b clocks of 0.68% sequence divergence per million years (MY) suggest that the split between the five major lineages happened approximately 12.4-17.6 MYA, and according to the lack of basal resolution of this monophyletic group probably the split of all lineages happened within a narrow time window.

Animals↗
PubMed1999

Oceanic minerals: their origin, nature of their environment, and significance.

The chemical and isotopic compositions of oceanic biogenic and authigenic minerals contain invaluable information on the evolution of seawater, hence on the history of interaction between tectonics, climate, ocean circulation, and the evolution of life. Important advances and greater understanding of (a) key minor and trace element cycles with various residence times, (b) isotopic sources and sinks and fractionation behaviors, and (c) potential diagenetic problems, as well as developments in high-precision instrumentation, recently have been achieved. These advances provided new compelling evidence that neither gradualism nor uniformitarianism can explain many of the new important discoveries obtained from the chemistry and isotopic compositions of oceanic minerals. Presently, the best-developed geochemical proxies in biogenic carbonates are 18O/16O and Sr/Ca ratios (possibly Mg/Ca) for temperature; 87Sr/86Sr for input sources, Cd/Ca and Ba/Ca ratios for phosphate and alkalinity concentrations, respectively, thus also for ocean circulation; 13C/12C for ocean productivity; B isotopes for seawater pH;, U, Th isotopes, and 14C for dating; and Sr and Mn concentrations for diagenesis. The oceanic authigenic minerals most widely used for chemical paleoceanography are barite, evaporite sulfates, and hydrogenous ferromanganese nodules. Marine barite is an effective alternative monitor of seawater 87Sr/86Sr, especially where carbonates are diagenetically altered or absent. It also provides a high-resolution record of seawater sulfate S isotopes, (evaporite sulfates only carry an episodic record), with new insights on factors affecting the S and C cycles and atmospheric oxygen. High-resolution studies of Sr, Nd, and Pb isotopes of well-dated ferromanganese nodules contain invaluable records on climate driven changes in oceanic circulation.

Journal Article↗
PubMed1996

An analysis of clinical seizure patterns and their localizing value in frontal and temporal lobe epilepsies.

The differentiation of frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE) is a clinical problem of major theoretical and practical importance. Current electroclinical classification is based on retrospective studies of highly selected patients. When applied to the presurgical evaluation of patients, it has poor specificity. The current study adopts a different and prospective approach to the analysis of ictal clinical manifestations and their value in differentiating FLE and TLE. Two hundred and fifty-two patients with partial epilepsy were selected according to criteria of focal abnormality and imaging, ictal EEG or interictal EEG or highly focal clinical pattern. A witnessed seizure description was obtained for each of their habitual seizures and the sequence of manifestations encoded and entered into a statistical cluster analysis to form a clinical classification of the 352 seizures identified, which comprised 14 clinical groups. Neuroimaging abnormalities were measured, using a template technique, and graded 0-3 according to extent of involvement of each region in the lesion, using standard anatomical divisions. A chi 2 analysis of lesion location against seizure type was performed to assess the strength of association of seizure types with specific cerebral regions. The distribution of interictal EEG spikes and ictal EEG onsets were assessed qualitatively. An independent analysis was also performed, comparing clinical seizure manifestations associated with lesions restricted to either frontal or temporal lobes. Of the 14 clinical groups, four were predominantly related to temporal lobe abnormalities: fear/olfactory/gustatory; absence with no focal symptoms; experiential and visual. Within these groups, 45 out of 58 lesional cases involved the temporal lobes (P<<0.001). A minority of seizures in these groups were associated with frontal lesions and these seizures were significantly more likely to involve version/posturing, without an intervening absence phase, than the temporal cases (P<0.001). Two groups were related to perirolandic abnormalities; somatosensory and Jacksonian clonic with 22 out of 24 lesional cases involving this region (P<0.001). Two other groups were related to the frontal lobes; version/posturing and motor agitation. Early focal tonic activity or head turning were associated with lateral premotor lesions (P<0.001) and ictal and interictal EEG showed strong frontal predominance. Seizures characterized by general motor agitation were associated with lesions of the orbitofrontal (eight out of thirteen cases) and frontopolar (six out of thirteen cases) cortices (P<0.001). Location of interictal EEG spikes and ictal EEG onsets were generally consistent with lesion sites and where there were discrepancies, EEG localization tended to be more diffuse than lesion localization, rather than frankly discordant. Analysis of manifestations associated with pure frontal and pure temporal lesions supported the results of the cluster analysis and also showed a significant association of oro-alimentary automatisms with temporal lobe abnormalities. There were no consistent differences between groups with different localizations in terms of seizure frequency or other characteristics of seizure timing, although very high seizure frequencies were seen more often in association with frontal lesions. Only one combination of different seizure types in the same patient occurred with statistical significance: absence and generalized motor seizures and pseudo generalized epilepsy. The results of this study suggest that relatively few seizures can be localized reliably on clinical grounds and that even in those seizure types where there is a statistically significant association with specific cortical areas, an important minority do not share the same associations. Analysis of the seizure evolution as well as initial symptoms may be of value in localizing some cases, but even here wide variation occurs...

Cluster Analysis↗
PubMed1985

Neutrophil specific granule deficiency.

Neutrophil specific granules are thought to be important in the evolution of the inflammatory response. Specific granules are preferentially released with minor membrane perturbation in vitro or in vivo, and secreted products probably have important effects on humoral and cellular components of inflammation. In vitro studies reveal that some secreted specific granule products activate the complement cascade to generate the chemoattractant C5a and the opsonin C3b, while other secreted products are selectively chemotactic for monocytes. Translocation of receptors for chemoattractants (fmet-leu-phe) and opsonins (C3bi) from specific granules or closely related organelles to the plasma membrane may play an important role in chemotaxis, adherence, and phagocytosis. Similar translocation of constituents of the electron transport chain involved in the respiratory burst (i.e. cytochrome b) probably plays a role in neutrophil oxidative metabolism and hydrogen peroxide generation. In vivo and in vitro studies of neutrophils from patients with congenital specific granule deficiency, acquired specific granule deficiency (thermal injury and neonates), or normal neutrophils experimentally depleted of nuclei and organelles support these conclusions. Thus, release of specific granule constituents appears to be important for amplification of the initial and subsequent phases of the inflammatory response.

Cell Aggregation↗
PubMed1990

Covalent structure of the minor monomeric beta-lactoglobulin II component from donkey milk.

The complete primary structure of the minor beta-lactoglobulin II component from donkey milk is presented. It has been established by amino-acid sequencing and mass-spectrometry analysis of intact protein and peptides obtained after enzymatic and chemical cleavages. The molecular mass and the pI of the protein are calculated to be 18,261 Da and 4.5 respectively. Despite the close structural similarity of the donkey and horse major beta-lactoglobulin I components, their minor beta-lactoglobulin II components show substantial differences in sequence. Most observed exchanges are clustered at residues 78-106 where only 6 amino-acid residues are conserved. The primary structure of donkey beta-lactoglobulin II reveals some unusual features of minor beta-lactoglobulins II and gives new light to the evolution of beta-lactoglobulins and other lipocalins involved in retinol binding or reproductive functions.

Amino Acid Sequence↗
PubMed1994

[Legal problems in headache].

Problems in expert opinion on headache patients are encountered in particular with cases of so-called posttraumatic headache. Symptoms in the vegetative field due to a head injury are characterized by a close time relationship with the accident or trauma. So is genuine post-traumatic headache. Like the so-called postconcussional syndrome, post-traumatic headache is very vaguely defined. To verify the causal connection between headache and head injury an in-depth neurological analysis is necessary. Lesions of intra- and extra-cranial structures sensitive to pain are apt to bring about subjective complaints in the form of headache. Severe craniocerebral injuries with persisting headache may be suggestive of chronic disturbances in cerebrospinal fluid circulation. On the other hand, extensive compound skull fractures and large cranial trephination defects rarely give rise to headache. Cephalgia occurring after cerebral concussions and minor cerebral contusions subside within a short period of time. The evolution of migraine following a head injury is extremely unusual. However, severe subjective complaints may be caused by traumatic subarachnoidal hemorrhage. An exceptional situation is that of neuralgic pain after an accident with injury to the head, especially in the wake of trigeminal nerve lesions. It seems important to mention the possibility of the combination of organic and psychological factors for cephalgia following craniocerebral trauma. Symptomatic headache generally does not cause special difficulties for expert opinion. However, more problems are encountered in the evaluation and appraisal of persistent headache and other subjective complaints in conversion neurosis and psychogenic disorders. Pensions for headache should only be considered in the most severe cases.

Brain Concussion↗
PubMed2006

The diallelic locus encoding the minor histocompatibility antigen HA-1 is evolutionarily conserved.

The polymorphic minor histocompatibility antigen HA-1 induces powerful T-cell alloreactivities with important consequences for graft-vs-tumor activity and development of graft-vs-host disease in patients after human leukocyte antigen-matched stem-cell transplantation (SCT). In view of possible translational animal studies, we analyzed the evolutionary conservation of the diallelic HA-1 locus in four mammalian species. Our results show that rodents do not encode the HA-1(H) allele, neither show polymorphism in this position on the HA-1 gene. Contrariwise, the HA-1(H) allele is present in non-human primate species and dogs. Interestingly, both the HA-1(H) T-cell epitope and its non-immunogenic counterpart HA-1(R) are present in the latter species. Thus, the HA-1 allelic polymorphism is conserved in evolution in primates and dogs.

Alleles↗
PubMed2003

The function of the chloride ion in photosynthetic oxygen evolution.

The involvement of Cl(-) and several other monovalent anions in photosynthetic oxygen evolution was studied using photosystem II membranes depleted of Cl(-) by dialysis. The results of these studies differ significantly from results obtained using other depletion methods. Binding studies with glycerol as a cryoprotectant confirm our previous observations with sucrose of two interconvertible binding states of photosystem II with similar activities and with slow or fast exchange, respectively, of the bound ion. With glycerol, Cl(-) depletion decreased the oxygen evolution rate to 55% of that with Cl(-) present without decreasing the quantum efficiency of the reaction, supporting our previous conclusion that oxygen evolution can proceed at high rates in the absence of Cl(-). Further, after Cl(-) depletion the S(2) state multiline signal displayed the same periodic appearance with the same signal yield after consecutive laser flashes as with Cl(-) present. Br(-), I(-), and NO(3)(-), although with different capacities to reactivate oxygen evolution, also showed two binding modes. I(-) inhibited when bound in the low-affinity, fast-exchange mode but activated in the high-affinity mode. A comparison of the EPR properties of the S(2) state with these anions suggests that the nature of the ion or the binding mode only has a minor influence on the environment of the manganese. In contrast, F(-) completely inhibited oxygen evolution by preventing the S(2) to S(3) transition and shifted the equilibrium between the g = 4.1 and multiline S(2) forms toward the former, which suggests a considerable perturbation of the manganese cluster. To explain these and earlier observations, we propose that the role of chloride in the water-splitting mechanism is to participate together with charged amino acid side chains in a proton-relay network, which facilitates proton transfer from the manganese cluster to the medium. The structural requirements likely to be involved may explain the sensitivity of oxygen evolution to Cl(-) depletion or other perturbations.

Anions↗
PubMed2001

Prevention of essential hypertension in minority populations.

The precursors of essential hypertension (EH) begin in childhood. If the etiology of the evolution of EH were discovered, interventions may be developed to lead to the primary prevention of EH. In particular, one ethnic group, African-Americans (Blacks), are at increased risk of development of EH in adulthood. Hemodynamic changes in response to stressors are termed measures of cardiovascular reactivity (CVR). Ethnic difference in CVR are known to exist; are these markers or mechanisms of EH evolution? Investigations are underway to discover the mechanism(s) of the excessive vasoconstriction which appears to be characteristic of the CVR responses in Blacks. These may lead to the pharmacologic, or non-pharmacologic, interventions which may be initiated in childhood and prevent EH in adults.

Journal Article↗
PubMed2006

Limited evolutionary conservation of imprinting in the human placenta.

The epigenetic phenomenon of genomic imprinting provides an additional level of gene regulation that is confined to a limited number of genes, frequently, but not exclusively, important for embryonic development. The evolution and maintenance of imprinting has been linked to the balance between the allocation of maternal resources to the developing fetus and the mother's well being. Genes that are imprinted in both the embryo and extraembryonic tissues show extensive conservation between a mouse and a human. Here we examine the human orthologues of mouse genes imprinted only in the placenta, assaying allele-specific expression and epigenetic modifications. The genes from the KCNQ1 domain and the isolated human orthologues of the imprinted genes Gatm and Dcn all are expressed biallelically in the human, from first-trimester trophoblast through to term. This lack of imprinting is independent of promoter CpG methylation and correlates with the absence of the allelic histone modifications dimethylation of lysine-9 residue of H3 (H3K9me2) and trimethylation of lysine-27 residue of H3 (H3K27me3). These specific histone modifications are thought to contribute toward regulation of imprinting in the mouse. Genes from the IGF2R domain show polymorphic concordant expression in the placenta, with imprinting demonstrated in only a minority of samples. Together these findings have important implications for understanding the evolution of mammalian genomic imprinting. Because most human pregnancies are singletons, this absence of competition might explain the comparatively relaxed need in the human for placental-specific imprinting.

Alleles↗