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Evolution of mouse chromosome 17 and the origin of inversions associated with t haplotypes.

Mouse t haplotypes are variant forms of chromosome 17 that exist at high frequencies in worldwide populations of several species of house mouse. They are known to differ from wild-type chromosomes with respect to two relative inversions referred to as proximal and distal. An untested assumption has been that these two inversions originated in the chromosomal lineage leading to present-day t haplotypes. To investigate the evolutionary origins of these inversions and the possibility of additional inversions, interspecific crosses were performed between Mus spretus or Mus abbotti and laboratory strains of Mus domesticus that carried wild-type and t haplotypes forms of chromosome 17. The results provide evidence for the existence of two additional nonoverlapping inversions--one between the proximal and distal inversions and one between the centromere and the proximal inversion. These four inversions span nearly the entire region of t haplotype recombination suppression. Considering the distribution of these inversions among the species studied as well as the organization of the D17Leh66 family of DNA elements, we infer that the proximal inversion occurred on the lineage leading to the common ancestor of M. domesticus and M. abbotti, and that the other three inversions occurred on the separate lineage leading to present-day t haplotypes. Alternative models for the evolution of t haplotypes are discussed in light of these findings.

Animals↗

Transient terminal U wave inversion as a more specific marker for myocardial ischemia.

Transient U wave inversion can be caused either by regional myocardial ischemia or by an elevation of systemic blood pressure. The characteristics of U wave inversion during chest pain attacks in 21 patients with variant angina were compared with those observed in 38 patients with hypertension without apparent ischemic heart disease. Differentiation was possible according to the ECG phase in which U wave inversion appeared. U wave inversion was considered to be significant if there was a discrete negative deflection of more than 0.05 mV within the TP segment. U wave inversion proceeded to positive deflection of U wave in patients with hypertension without ischemic heart disease (initial U wave inversion). In contrast, inverted U wave occurred after positive U wave deflection during attacks in patients with variant angina (terminal U wave inversion). When cold pressor test was performed in patients with variant angina during treatment with calcium entry blockers, no patient had either anginal attacks or ischemic ST-segment deviation, but 9 of 21 patients (43%) had transient initial U wave inversion, which was followed by positive U wave deflection. U wave inversion can be classified as initial U wave inversion and terminal U wave inversion according to the phasic relationship to positive U wave deflection; the latter is observed in association with regional myocardial ischemia. The former seems to be related to elevated blood pressure rather than to myocardial ischemia.

Adult↗

Correction of errors caused by imperfect inversion pulses in MR imaging measurement of T1 relaxation times.

Spin-lattice (T1) relaxation times were measured by an inversion-recovery magnetic resonance imaging method with a slice-selective inversion pulse (SIP), a non-selective rectangular inversion pulse (RIP), or a B1-insensitive adiabatic inversion pulse (AIP). Data analysis either assumed perfect inversion (two-parameter fit) or allowed for imperfect inversion (three-parameter fit). Imperfect inversion pulses caused low T1 values in phantoms with a two-parameter fit, while three-parameter T1 estimates were accurate over the range 430-2670 ms. A difference of approximately 10% between two-parameter and three-parameter T1 values in normal human brain tissue was attributed to B1 inhomogeneity with the slice-selective inversion pulse and rectangular inversion pulse, to the slice profile with the slice-selective inversion pulse, and to T2 effects for the adiabatic inversion pulse. Any T1 method that relies on accurate flip angles may have a significant systematic error in vivo. Phantom accuracy does not ensure accuracy in vivo, because phantoms may have a more homogeneous B1 field and a longer T2 than do biological samples.

Adult↗

Chiral inversion of drugs: coincidence or principle?

2-arylpropionic acid derivatives are probably the most frequently cited drugs exhibiting the phenomenon that is best known as chiral inversion. One enantiomer of drug is converted into its antipode either in the presence of a solvent or more often in inner environment of an organism. Mechanistic studies of the metabolic chiral inversion were carried out for several drugs from NSAIDs, and a model of this inversion was suggested and subsequently confirmed. The chiral inversion of NSAIDs has been intensively studied in the context of the pharmacological and toxicological consequences. However, the group of NSAIDs is not the sole group of drugs in which the inversion phenomenon can be observed. There exist several other drugs that also display chiral inversion of one or even both of their enantiomers. These drugs belong to different pharmacotherapeutic groups as monoamine oxidase inhibitors, antiepileptic drugs, drugs used in the treatment of hyperlipoproteinemia or drugs that are effective in the treatment of leprosy. Moreover, some chiral or prochiral drugs are metabolized to give chiral metabolites that undergo chiral inversion too, which can have direct impact on pharmacological properties or toxicity of the drug. As the process of chiral inversion is affected by several factors, so the intensity of chiral inversion of individual substances and at different conditions can differ considerably. Interspecies differences and types of tissue are reported to be the main factors that were recognized to play the key role in the process of chiral inversion. Some of more recent studies have revealed that several other factors, such as the route of administration or interaction with other xenobiotics, can influence the enantiomeric conversion, too. Chiral inversion does not seem to be a phenomenon connected with only several drugs from some unique group of 2-arylpropionic acid derivatives: it is also observed in drugs with rather different chemical structures and is much more frequent than it can be realized.

Animals↗

Comparing Levovist-enhanced pulse inversion harmonic imaging and ferumoxides-enhanced MR imaging of hepatic metastases.

OBJECTIVE: The aim of this study was to compare the sensitivity of pulse inversion harmonic digital sonography, unenhanced transabdominal sonography, and ferumoxides-enhanced MR imaging in the depiction of liver metastases. In addition, pulse inversion harmonic digital sonography was performed at different scanning times after Levovist injection to define the best phase for depiction. SUBJECTS AND METHODS: Twenty-six consecutive patients with findings of extrahepatic primary malignancies and liver metastases suspected on transabdominal sonography were examined with both pulse inversion harmonic imaging and ferumoxides-enhanced MR imaging within a 7-day period. Pulse inversion harmonic imaging was performed before and at 20, 100, and 180 sec after a bolus injection of Levovist. MR imaging was performed before and after ferumoxides administration, using breath-hold gradient-recalled echo T1-weighted and turbo spin-echo short tau inversion recovery T2-weighted sequences. Two radiologists independently evaluated image quality, and the number, location, and diameter of lesions scanned using both techniques. Intraoperative sonography or at least 8-month follow-up confirmed the lesions depicted. Analyses included Wilcoxon's signed rank test and Interclass correlation test. RESULTS: Levovist-enhanced pulse inversion harmonic imaging revealed 104 metastases on the first scan after contrast injection, 126 on the second scan, and 118 on the third, compared with 66 on the unenhanced scan. Pulse inversion harmonic digital sonography depicted 90% of lesions shown on ferumoxides-enhanced MR imaging (140 metastases) (p = 0.001). CONCLUSION: Levovist-enhanced pulse inversion harmonic digital sonography is a sensitive technique for depiction of liver metastases. Pulse inversion harmonic digital sonography may have a potential role in imaging patients with possible metastatic involvement of the liver. Further studies are needed to define its place in the workup of these patients. At present, ferumoxides-enhanced MR imaging, being more sensitive, must be performed in all patients in whom pulse inversion harmonic digital sonography is not conclusive or when after pulse inversion harmonic digital sonography, patients remain eligible for surgery.

Adult↗

Agonist-induced modulation of inverse agonist efficacy at the beta 2-adrenergic receptor.

Sustained stimulation of several G protein-coupled receptors is known to lead to a reduction in the signaling efficacy. This phenomenon, named agonist-induced desensitization, has been best studied for the beta 2-adrenergic receptor (AR) and is characterized by a decreased efficacy of beta-adrenergic agonists to stimulate the adenylyl cyclase activity. Recently, several beta-adrenergic ligands were found to inhibit the spontaneous agonist-independent activity of the beta 2AR. These compounds, termed inverse agonists, have different inhibitory efficacies, ranging from almost neutral antagonists to full inverse agonists. The current study was undertaken to determine whether, as is the case for agonists, desensitization can affect the efficacies of inverse agonists. Agonist-promoted desensitization of the human beta 2AR expressed in Sf9 cells potentiated the inhibitory actions of the inverse agonists, with the extent of the potentiation being inversely proportional to their intrinsic activity. For example, desensitization increased the inhibitory action of the weak inverse agonist labetalol by 29%, whereas inhibition of the spontaneous activity by the strong inverse agonist timolol was not enhanced by the desensitizing stimuli. Interestingly, dichloroisoproterenol acted stochastically as either a weak partial agonist or a weak inverse agonist in control conditions but always behaved as an inverse agonist after desensitization. These data demonstrate that like for agonists, the efficacies of inverse agonists can be modulated by a desensitizing treatment. Also, the data show that the initial state of the receptor can determine whether a ligand behaves as a partial agonist or an inverse agonist.

Adenylyl Cyclases↗

Direct evidence for suppression of recombination within two pericentric inversions in humans: a new sperm-FISH technique.

Crossover within a pericentric inversion produces reciprocal recombinant chromosomes that are duplicated/deficient for all chromatin distal to the breakpoints. In view of this fact, a new technique is presented for estimating the frequency of recombination within pericentric inversions. YAC probes were selected from within the q- and p-arm flanking regions of two human inversions, and two-color FISH analysis was performed on sperm from heterozygous inversion carriers. A total of 6,006 sperm were analyzed for chromosome 1 inversion (p31q12), and 3,168 were analyzed for chromosome 8 inversion (p23q22). Both inversions displayed suppression of crossing-over, although the amount of suppression differed between the two inversions. The recombination frequency of 13.1% recorded for chromosome 8 inversion was similar to the frequency of 11.4% previously estimated by the human/hamster-fusion method. For chromosome 1 inversion, the recombination frequency of 0. 4% reported here was below the limits of detection of the fusion technique. The simplicity of the FISH technique and the ease of scoring facilitate analysis of a sample-population size much larger than previously had been possible.

Animals↗

The fertility effects of pericentric inversions in Drosophila melanogaster.

Heterozygotes for pericentric inversions are expected to be semisterile because recombination in the inverted region produces aneuploid gametes. Newly arising pericentric inversions should therefore be quickly eliminated from populations by natural selection. The occasional polymorphism for such inversions and their fixation among closely related species have supported the idea that genetic drift in very small populations can overcome natural selection in the wild. We studied the effect of 7 second-chromosome and 30 third-chromosome pericentric inversions on the fertility of heterokaryotypic Drosophila melanogaster females. Surprisingly, fertility was not significantly reduced in many cases, even when the inversion was quite large. This lack of underdominance is almost certainly due to suppressed recombination in inversion heterozygotes, a phenomenon previously observed in Drosophila. In the large sample of third-chromosome inversions, the degree of underdominance depends far more on the position of breakpoints than on the inversion's length. Analysis of these positions shows that this chromosome has a pair of "sensitive sites" near cytological divisions 68 and 92: these sites appear to reduce recombination in a heterozygous inversion whose breakpoints are nearby. There may also be "sensitive sites" near divisions 31 and 49 on the second chromosome. Such sites may be important in initiating synapsis. Because many pericentric inversions do not reduce the fertility of heterozygotes, we conclude that the observed fixation or polymorphism of such rearrangements in nature does not imply genetic drift in very small populations.

Aneuploidy↗

Genome-wide diversity of chromosomal inversions and their disease relationships.

Chromosomal inversions shape evolution and are implicated in human disease, yet their effects on genomic variation and health outcomes remain poorly understood. We analyze genome-wide human inversion polymorphisms, contrasting single-event and recurrent loci. Inversion recurrence is validated using structured-coalescent simulations. We show that single-event inversions evolve in near-complete isolation: inverted haplotypes show ~16-fold lower diversity and strong differentiation from direct haplotypes (median FST = 0.33). By contrast, recurrent inversions maintain gene flow, resulting in similar diversity across orientations and ~4-fold lower differentiation. We further find marked differences in coding sequence conservation between single-event and recurrent inversions. Using the NIH All of Us biobank, we impute inversions and identify four inversions with significant disease associations. Notably, the 17q21 inversion is associated with reduced risk of cognitive decline (OR=0.919) and breast cancer (OR=0.910) but with increased obesity risk (OR=1.097), consistent with pleiotropic selection. These findings establish inversions as major drivers of human genetic diversity and disease, with evolutionary outcomes critically dependent on recurrence.

Evolution↗

Are chromosomal inversions induced by transposable elements? A paradigm from the malaria mosquito Anopheles gambiae.

Chromosomal rearrangements abound in nature and can be studied in detail in organisms with polytene chromosomes. In Drosophila and in Anopheline mosquitoes most speciation processes seem to be associated with the establishment of chromosomal rearrangements, particularly of paracentric inversions. It is not known what triggers inversions in natural populations. In the laboratory inversions are commonly generated by X-rays, mutagens or after the activity of certain transposable elements (TEs). The Anopheles gambiae complex is comprised of six sibling species, each one characterized by the presence of fixed paracentric inversions on their chromosomes. Two of these, An. gambiae s.s. and An. arabiensis, are the most important vectors of human malaria and are structured into sub-populations, each carrying a characteristic set of polymorphic chromosomal inversions. We have cloned the breakpoints of the naturally occurring polymorphic inversion In(2R)d' of An. arabiensis. Analysis of the surrounding sequences demonstrated that adjacent to the distal breakpoint lies a transposable element that we called Odysseus. Characteristics of Odysseus' terminal region and its cytological distribution in different strains as well as within the same strain indicate that Odysseus is an actively transposing element. The presence of Odysseus at the junction of the naturally occurring inversion In(2R)d' suggests that the inversion may be the result of the TEs activity. Cytological evidence from Drosophila melanogaster has also implicated the hobo transposable element in the generation of certain Hawaiian endemic inversions. This picture supports the hypothesis of the important role of TEs in generating natural inversions.

Animals↗

[Acute complete uterine inversion--care report].

OBJECTIVES: Acute puerperal uterine inversion is a rare but very feared obstetrical complication. It determines an almost immediate shock and serious metrorrhagia. It is a introflexion of parietes uteri which takes place during the third stage of labor or during the first hours of puerperium. It can be distinguished in inversion of I, II or III degree according to the zone concerned by the introflexion: only the fundus of the uterus, all the corpus emerging in the vagina or the entirety of the uterus coming out from the vulvar orifice. RESULTS: This is report a case of inversion of the uterus during third stage of labor in multiparous aged 24 years admitted to Department of Gynecology & Obstetric in Hospital of Słupsk. The uterine III degree inversion was spontaneous during third stage of labor and was immediately diagnosed. Manual manipulation was attempted immediately to reverse the inversion but it was not successful. Because patient fell in cardiovascular shock she was resusciated and the inverted uterus repositioned using Huntington's method under general anaesthesia. After intra-abdominal repositioning of the uterus the placenta was removed manually and intramural injection of oxitocine was done to avoid immediate relapse. Whole obstetrical procedure was carried out within one-half hour after inversion. CONCLUSIONS: Although uncommon, in left unrecognized, uterine inversion will result in severe hemorrhage and shock, leading to maternal death. Manual manipulation should be attempted immediately to reverse the inversion. In the most resistant of inversions, surgical correction might be required. Following inversion of the uterus, further normal pregnancies can be expected.

Acute Disease↗

Factor VIII gene inversions in severe hemophilia A: results of an international consortium study.

Twenty-two molecular diagnostic laboratories from 14 countries participated in a consortium study to estimate the impact of Factor VIII gene inversions in severe hemophilia A. A total of 2,093 patients with severe hemophilia A were studied; of those, 740 (35%) had a type 1 (distal) factor VIII inversion, and 140 (7%) showed a type 2 (proximal) inversion. In 25 cases, the molecular analysis showed additional abnormal or polymorphic patterns. Ninety-eight percent of 532 mothers of patients with inversions were carriers of the abnormal factor VIII gene; when only mothers of nonfamilial cases were studied, 9 de novo inversions in maternal germ cells were observed among 225 cases (approximately 1 de novo maternal origin of the inversion in 25 mothers of sporadic cases). When the maternal grandparental origin was examined, the inversions occurred de novo in male germ cells in 69 cases and female germ cells in 1 case. The presence of factor VIII inversions is not a major predisposing factor for the development of factor VIII inhibitors; however, slightly more patients with severe hemophilia A and factor VIII inversions develop inhibitors (130 of 642 [20%]) than patients with severe hemophilia A without inversions (131 of 821 [16%]).

Blotting, Southern↗

A "voice inversion effect?".

Voice is the carrier of speech but is also an "auditory face" rich in information on the speaker's identity and affective state. Three experiments explored the possibility of a "voice inversion effect," by analogy to the classical "face inversion effect," which could support the hypothesis of a voice-specific module. Experiment 1 consisted of a gender identification task on two syllables pronounced by 90 speakers (boys, girls, men, and women). Experiment 2 consisted of a speaker discrimination task on pairs of syllables (8 men and 8 women). Experiment 3 consisted of an instrument discrimination task on pairs of melodies (8 string and 8 wind instruments). In all three experiments, stimuli were presented in 4 conditions: (1) no inversion; (2) temporal inversion (e.g., backwards speech); (3) frequency inversion centered around 4000 Hz; and (4) around 2500 Hz. Results indicated a significant decrease in performance caused by sound inversion, with a much stronger effect for frequency than for temporal inversion. Interestingly, although frequency inversion markedly affected timbre for both voices and instruments, subjects' performance was still above chance. However, performance at instrument discrimination was much higher than for voices, preventing comparison of inversion effects for voices vs. non-vocal stimuli. Additional experiments will be necessary to conclude on the existence of a possible "voice inversion effect."

Acoustic Stimulation↗

Some implications of receptor theory for in vivo assessment of agonists, antagonists and inverse agonists.

Drug effects can be classified into three major phenotypes: agonist, antagonist and inverse agonist. Agonist and inverse agonist effects are associated with receptor activation and inactivation, respectively, whereas antagonism implies that a drug produces no effect when administered alone but blocks the effects of agonists and inverse agonists. Attention has only recently begun to focus on the theoretical and clinical implications of inverse agonists, and studies of inverse agonism have also stimulated revisions in receptor theory. This commentary addresses two specific issues related to the application of receptor theory to studies of inverse agonists in vivo. First, principles of receptor theory suggest that increasing drug doses produce a graded pharmacological stimulus that is transduced by receptor-containing tissue into a biological response. However, assays vary in their ability to detect those responses, and any given assay provides only a narrow window on the full range of underlying drug effects. Consequently, in vivo assessment of inverse agonists will benefit from development of assays sensitive to graded inverse agonist effects. Second, detection of inverse agonist effects requires some preexisting level of receptor activity (or tone). This tone can result from at least two sources: (a) endogenous ligands for the receptor, or (b) constitutive receptor activity. Strategies for discriminating these two sources of tone will also contribute to the in vivo assessment of inverse agonist effects. Studies with intermediate efficacy ligands may be especially helpful in this regard, because their effects are differentially influenced by endogenous agonist tone versus constitutive receptor tone.

Models, Theoretical↗

Genetic methods for analysis and manipulation of inversion mutations in bacteria.

A number of genetic methods for the isolation, characterization and manipulation of large chromosomal inversions in Salmonella typhimurium are described. One inversion-carrying mutant is characterized in detail and used to demonstrate a number of unique genetic properties of bacterial inversions. --Contrary to expectation, it was found that large inversion mutations can be repaired by generalized transduction. The repair results from the simultaneous introduction of two wild-type transduced fragments into a single recipient cell. Homologous recombination between the two transduced fragments and the two inversion breakpoints causes the inverted segment to be reinverted. This results in regeneration of the wild-type orientation of this chromosome segment. Similar recombination events allow a large inversion mutation to be introduced into a wild-type strain; two transduced fragments from an inversion strain cause recombination events resulting in inversion of a large chromosome segment. --Genetic methods for mapping the extent of a large inversion mutation by generalized transduction are described and tested. The methods are operationally simple and allow good resolution of the two inversion breakpoints.

Chromosome Mapping↗

The evolutionary history of Drosophila buzzatii. XXXV. Inversion polymorphism and nucleotide variability in different regions of the second chromosome.

Inversions are portions of a chromosome where the gene order is reversed relative to a standard reference orientation. Because of reduced levels of recombination in heterokaryotypes, inversions have a potentially important effect on patterns of nucleotide variability in those genomic regions close to, or included in, the inverted fragments. Here we report sequence variation at three anonymous regions (STSs) located at different positions in relation to second-chromosome inversion breakpoints in 29 isochromosomal lines derived from an Argentinean population of Drosophila buzzatii. In agreement with previous findings in Drosophila, gene flux (crossing over and/or gene conversion) between arrangements seems to appreciably increase as we approach the middle sections of inversion 2j, and patterns of nucleotide variability within, as well as genetic differentiation between chromosome arrangements, are comparable to those observed at the molecular marker outside the inverted fragments. On the other hand, nucleotide diversity near the proximal breakpoint of inversion 2j is reduced when contrasted with that found at the other regions, particularly in the case of derived inverted chromosomes. Using the data from the breakpoint, we estimate that the inversion polymorphism is approximately 1.63 N generations old, where N is the effective population size. An excess of low-frequency segregating polymorphisms is detected; mostly in the ancestral 2st arrangement and probably indicating a population expansion that predates the coalescent time of inversion 2j. Heterogeneity in mutation rates between the markers linked to the inversions may be sufficient to explain the different levels of nucleotide diversity observed. When considered in the context of other studies on patterns of variation relative to physical distance to inversion breakpoints, our data appear to be consistent with the conclusion that inversions are unlikely to be "long-lived" balanced polymorphisms.

Animals↗

Effects of two gravity inversion methods on heart rate, systolic brachial pressure, and ophthalmic artery pressure.

The purpose of this study was to investigate the effects of two static gravity inversion methods with either ankle or thigh suspension on heart rate (HR), systolic brachial pressure (SBP), and ophthalmic artery pressure (OAP). Twenty healthy subjects were assigned randomly to one of two treatment groups of 10 subjects each. Each group completed a 25-minute protocol with two 5-minute inversion periods. The research attempted to control for treatment anxiety and for the effects of ocular plethysmography (the procedure used to measure OAP). A 2 X 2 multivariate analysis of variance for repeated measures was used to analyze the differences of cardiovascular change between the two inversion methods. The hypothesis that the subjects' HRs, SBPs, and OAPs would not differ between ankle and thigh suspension methods for five minutes of inversion was not rejected. Leg position did not affect the HR or arterial responses during full static inversion. Gravity inversion produced no significant changes in HR and SBP between 2.5 and 5 minutes of inversion. Arterial pressures measured at 5 minutes of static inversion did not differ from arterial pressures measured between 2.5 and 5 minutes, but because of increases in OAP during inversion, ocular safeguards are recommended for subjects during inversion.

Adult↗

Effects of experimental and modeling errors on electrocardiographic inverse formulations.

The inverse problem of electrocardiology aims to reconstruct the electrical activity occurring within the heart using information obtained noninvasively on the body surface. Potentials obtained on the torso surface can be used as input for the inverse problem and an electrical image of the heart obtained. There are a number of different inverse algorithms currently used to produce electrical images of the heart. The relative performances of these inverse algorithms at this stage is largely unknown. Although there have been many simulation studies investigating the accuracy of each of these algorithms, to date, there has been no comprehensive study which compares a wide variety of inverse methods. By performing a detailed simulation study, we compare the performances of epicardial potential [Tikhonov, Truncated singular value decomposition (TSVD), and Greensite] and myocardial activation-based (critical point) inverse simulations along with different methods of choosing the appropriate level of regularization (optimal, L-curve, composite residual and smoothing operator, zero-crossing) to apply to each of these inverse methods. We also examine the effects of a variety of signal error, material property error, geometric error and a combination of these errors on each of the electrocardiographic inverse algorithms. Results from the simulation study show that the activation-based method is able to produce solutions which are more accurate and stable than potential-based methods especially in the presence of correlated errors such as geometric uncertainty. In general, the Greensite-Tikhonov method produced the most realistic potential-based solutions while the zero-crossing and L-curve were the preferred method for determining the regularization parameter. The presence of signal or material property error has little effect on the inverse solutions when compared with the large errors which resulted from the presence of any geometric error. In the presence of combined Gaussian and correlated errors representing conditions which may be encountered in an experimental or clinical environment, there was less variability between potential-based solutions produced by each of the inverse algorithms.

Algorithms↗