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PubMed1998

Reverse gyrase from the hyperthermophilic bacterium Thermotoga maritima: properties and gene structure.

The hyperthermophilic bacterium Thermotoga maritima MSB8 possesses a reverse gyrase whose enzymatic properties are very similar to those of archaeal reverse gyrases. It catalyzes the positive supercoiling of the DNA in an Mg2+- and ATP-dependent process. Its optimal temperature of activity is around 90 degrees C, and it is highly thermostable. We have cloned and DNA sequenced the corresponding gene (T. maritima topR). This is the first report describing the analysis of a gene encoding a reverse gyrase in bacteria. The T. maritima topR gene codes for a protein of 1,104 amino acids with a deduced molecular weight of 128,259, a value in agreement with that estimated from the denaturing gel electrophoresis of the purified enzyme. Like its archaeal homologs, the T. maritima reverse gyrase exhibits helicase and topoisomerase domains, and its sequence matches very well the consensus sequence for six reverse gyrases now available. Phylogenetic analysis shows that all reverse gyrases, including the T. maritima enzyme, form a very homogeneous group, distinct from the type I 5' topoisomerases of the TopA subfamily, for which we have previously isolated a representative gene in T. maritima (topA). The coexistence of these two distinct genes, coding for a reverse gyrase and an omega-like topoisomerase, respectively, together with the recent description of a gyrase in T. maritima (O. Guipaud, E. Marguet, K. M. Noll, C. Bouthier de la Tour, and P. Forterre, Proc. Natl. Acad. Sci. USA 94:10606-10611, 1977) addresses the question of the control of the supercoiling in this organism.

Amino Acid Sequence↗
PubMed1978

Binding of tRNA to reverse transcriptase of RNA tumor viruses.

The interaction of tRNA with the reverse transcriptase (RNA-dependent DNA polymerase) of mammalian RNA viruses, such as Moloney murine leukemia virus and simian sarcoma virus, has been studied. Whereas the purified reverse transcriptase of mammalian viruses sedimented in glycerol gradients as a globular protein with a molecular weight of 70,000, after interaction with tRNA the enzyme cosedimented with a protein of 150,000 molecular weight. The twofold increase in molecular weight could be a result of either two reverse transcriptase molecules complexed with a tRNA or, alternatively, several tRNA molecules bound to a single enzyme polypeptide. The enzyme complexes were dissociated in part upon degradation of the tRNA moiety by pancreatic RNase A. The reverse transcriptase released from virions of Moloney murine leukemia virus, simian sarcoma virus, and avian myeloblastosis virus, by nonionic detergent, migrated faster on glycerol gradients than purified enzyme preparation. This phenomenon was probably due to complex formation between part of the virion enzyme and the tRNA, which is endogenous in virions. Addition of exogenous tRNA was needed, however, to quantitatively complex all the virion reverse transcriptase of Moloney murine leukemia virus and simian sarcoma viruses. The reverse transcriptase of Moloney murine leukemia virus did not show tRNA species specificity in the binding reaction when glycerol gradients were used for assay. Thus, several tRNA species of Escherichia coli, yeast, chicken, and rat origin were able to complex with the enzyme. The species specificity in the interaction between tRNA and avian myeloblastosis virus reverse transcriptase was also examined. We demonstrated that under our experimental conditions, this enzyme binds different tRNA species of E. coli and yeast as well as tRNA of chicken origin.

Animals↗
PubMed1983

Mechanism of action of the endonuclease associated with the alpha beta and beta beta forms of avian RNA tumor virus reverse transcriptase.

Preparations of the alphabeta and the betabeta forms of reverse transcriptase from the Prague C strain of Rous sarcoma virus grown in chicken embryo fibroblasts, the alphabeta and the betabeta forms of the enzyme from the B77 strain of Rous sarcoma virus grown in duck embryo fibroblasts, and the alphabeta form of reverse transcriptase from avian myeloblastosis virus have been analyzed. All these enzyme preparations contain a Mn(2+) -activated endonuclease activity. The betabeta form of enzyme, in addition, contains a Mg(2+) -dependent endonuclease. Such an activity is barely detectable in the alphabeta form of enzymes. The endonuclease associated with reverse transcriptase introduces single- and double-strand breaks containing 3' OH and 5' P termini into RF I DNA. The conversion of RF I DNA to RF III DNA is more readily catalyzed by the betabeta form of reverse transcriptase. In contrast to a recently published report by Hizi et al. (J. Virol 41:974-981, 1982), we have failed to detect the conversion of RF I DNA to covalently closed relaxed circles (RF IV DNA) by any of the alphabeta form of enzymes tested. RF IV DNA was not produced by the betabeta form of reverse transcriptase either. We conclude that topoisomerization is not an intrinsic activity of reverse transcriptase. Although the conversion of RF I DNA to RF II DNA was found to be rapid, the endonuclease associated with reverse transcriptase acted slowly on RF II, RF III, and RF IV DNAs. Circular and linear single-stranded DNAs were also susceptible to cleavage by the endonuclease at a rate comparable to nicking of RF I DNA. This pattern of activity suggests that the endonuclease cleaves the RF I DNA in the single-stranded regions of the DNA induced by its supercoiling. The preference of the alphabeta and the betabeta forms of the endonuclease for viral DNA was tested with Rous-associated virus type 2 and Rous sarcoma virus transformation-defective Schmidt-Ruppin B strain DNA molecularly cloned in plasmid pBR322 and M13 DNA vectors, respectively. The rate of nicking of RF I DNA containing viral DNA or partial sequences of viral DNA with one or two tandem long terminal repeats was the same as when these sequences were not present in the host vectors. A similar lack of preference was observed with single-stranded M13 DNAs.

Avian Leukosis Virus↗
PubMed1989

Identification of a doubly spliced viral transcript joining the separated domains for putative protease and reverse transcriptase of hepatitis B virus.

Hepatitis B virus (HBV), like retroviruses, replicates through reverse transcription. However, the identity and mechanism for the synthesis of HBV reverse transcriptase remain unknown. The open reading frame (ORF) for HBV putative reverse transcriptase (pol), as a consequence of overlapping with the whole ORF of envelope proteins (hepatitis B surface antigens), includes a hypervariable region at the N terminus. Thus, compared with retroviruses, it is unlikely that HBV reverse transcriptase is translated from complete pol ORF in the full-length pregenomic RNA. We have now detected in infected human livers a novel doubly spliced RNA in which one splicing event removed the hypervariable region of the pol gene but retained the conserved region homologous to retroviral reverse transcriptase. The other splicing event deleted the central region of hepatitis B core antigen and thus brought the protease domain which is important for maturation of reverse transcriptase close to that of pol. For this sequence organization, the spliced RNA as the possible template for the synthesis of HBV reverse transcriptase is discussed.

Base Sequence↗
PubMed1994

A specific orientation of RNA secondary structures is required for initiation of reverse transcription.

The 5' end of avian retrovirus RNA near the primer-binding site (PBS) forms two secondary structures, the U5-inverted repeat (U5-IR) and the U5-leader stems, and contains a 7-nucleotide sequence that anneals to the T psi C loop of the tRNA(Trp) primer. Mutations that disrupt any of these base pair interactions cause defects in initiation of reverse transcription both in vivo and in vitro (D. Cobrinik, A. Aiyar, Z. Ge, M. Katzman, H. Huang, and J. Leis, J. Virol. 65:3864-3872, 1991; A. Aiyar, D. Cobrinik, Z. Ge, H.-J. Kung, and J. Leis, J. Virol. 66:2464-2472, 1992). We have now examined the effect of perturbing the non-base-paired intervening "spacer" sequences between these secondary-structure elements. Small deletions or insertions in these intervening sequences decreased initiation of reverse transcription in vitro. In contrast, base substitutions, which maintain the spacing distances between the structures, had no detectable effect. Additionally, a small deletion at the 3' end of the PBS caused a significant decrease in initiation of reverse transcription whereas substitution mutations again had no effect. Together, these results indicate that reverse transcriptase forms a complex in which the different structural elements are maintained in a specific orientation that is required for efficient initiation of reverse transcription. Specific sequence recognition of the duplex structures by reverse transcriptase is also required since mosaic RNAs that combine the human immunodeficiency virus type 1 PBS with avian sequences is not efficiently utilized for reverse transcription even though the primer used can anneal to the substituted PBS.

Avian Sarcoma Viruses↗
PubMed1996

Effects of 3'-deoxynucleoside 5'-triphosphate concentrations on chain termination by nucleoside analogs during human immunodeficiency virus type 1 reverse transcription of minus-strand strong-stop DNA.

We have compared the effects of nucleoside analogs in quiescent and phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC) exposed to human immunodeficiency virus type 1 (HIV-1) with those of their triphosphorylated derivatives in cell-free HIV-1 reverse transcription assays. We observed a substantial decrease in synthesis of early minus-strand proviral DNA products in HIV-1-infected, quiescent PBMC exposed to each of 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxyinosine (ddI), and 2',3'-dideoxy-3'-thiacytidine (3TC), in comparison with nontreated, infected controls. In contrast, no such diminution was observed when PHA-stimulated, HIV-1-infected PBMC were treated with the same drugs. This result was attributed to previously reported findings that PHA-stimulated PBMC possessed larger deoxynucleoside triphosphate (dNTP) pools than quiescent cells did. To further investigate this subject, a cell-free HIV-1 reverse transcription reaction involving HIV-1 RNA genomic template, recombinant purified HIV-1 reverse transcriptase, all four dNTPs and either tRNA3Lys or a deoxyoligonucleotide as primer was used to monitor chain termi-nation mediated by 2',3'-dideoxynucleoside triphosphates (ddNTPs) during synthesis of minus-strand strong-stop DNA. Augmented chain termination was observed with decreasing concentrations of both ddNTP and dNTP when the ratio of dNTP to ddNTP was fixed. We also found that both the number and strength of reverse transcription pause sites were increased at low concentrations of dNTPs and when a deoxyoligonucleotide primer was used in place of the cognate primer, tRNA3Lys. Preferential incorporation of ddATP was observed dur-ing reverse transcription opposite a distinct pause site in a short synthetic RNA template. These results con-firm the notion that the antiviral activities of ddNTP are dependent on both cellular dNTP pools and the state of cellular activation. Pausing of HIV-1 reverse transcriptase during reverse transcription, altered by dNTP concentrations, may be a mechanism that controls the position and extent of incorporation of nucleoside analogs.

Antiviral Agents↗
PubMed1998

Reversal of hypoaesthesia by nerve block, or placebo: a psychologically mediated sign in chronic pseudoneuropathic pain patients.

OBJECTIVES: To gain understanding of the mechanism and meaning of improvement of hypoaesthesia after a diagnostic intervention, and of the nature of the population that displays such a sign. METHODS: Patients with chronic "neuropathic" pain underwent rigorous clinical and laboratory investigations, including placebo controlled local anaesthetic block. Patients displaying profound regional cutaneous hypoaesthesia and pain entered the study through either of two criteria: (a) reversal of hypoaesthesia after diagnostic block, (b) nerve injury as the cause of hypoaesthesia and pain. The semeiology displayed by these patients together with the behaviour of their sensory phenomena in response to blocks were compared. Three groups were expected: (1) patients with "neuropathic" pain with profound hypoaesthesia reversed by block, but without neuropathy; (2) patients whose hypoaesthesia did not reverse and who had neuropathy as the cause of their sensory dysfunction; and (3) patients whose hypoaesthesia reversed, and had neuropathy. RESULTS: Two groups emerged: (1) patients with profound hypoaesthesia reversed by block, but without neuropathy (27 patients), and (2) patients whose hypoaesthesia did not reverse and who had a neuropathy (13 patients). No patient with neuropathy was found whose cutaneous hypoaesthesia improved with block. The first group displayed the sensory-motor characteristics of psychogenic pseudoneuropathy. The semeiology of the second group was in keeping with organic neuropathy and displayed no pseudoneurological features. Spontaneous pain was relieved by placebo in 66.6% of the patients in groupl and 53.8% in group 2. CONCLUSIONS: Such reversal of hypoaesthesia is due to a placebo effect, acting on a psychogenic symptom because: (a) 27 of 27 patients in which the sign occurred had absence of nerve disease behind the "neuropathic" symptoms, (b) In 26 of 27 patients the area of hypoaesthesia was non-anatomical, (c) 16 of 27 patients had other sensory-motor signs that could not be explained as a result of organic pathology (give way weakness and punctual denial of hypoaesthesia), and (d) the phenomenon was not found in patients with organic neuropathy.

Adult↗
PubMed2002

Potentially reversible conditions in 1000 consecutive memory clinic patients.

OBJECTIVES: To investigate the prevalence and classification of potentially reversible conditions in a prospective memory clinic cohort of younger and elderly patients with cognitive symptoms. PATIENTS: 1000 consecutive patients referred during a period of 54 months to a university hospital multidisciplinary memory clinic based in neurology. METHODS: All patients were referred for diagnostic evaluation and treatment of cognitive symptoms. The multidisciplinary staff prospectively established a standardised consensus report for each patient based on the results of clinical and ancillary investigations with classification of cognitive profile, primary underlying cause, and concomitant conditions. RESULTS: The mean age of the patients was 66.1 years (range 17-98) and 43% met diagnostic criteria for dementia. A potentially reversible primary aetiology for cognitive symptoms was identified in 19% and a potentially reversible concomitant condition in 23% of all patients. In the subgroup of patients with dementia, 4% had a potentially reversible primary aetiology. Careful clinical examination, routine laboratory tests, and cranial computed tomography identified most of these conditions. CONCLUSIONS: Reversible conditions are most often encountered in patients with mild cognitive disturbances. Although treatment may not always result in full reversal of cognitive symptoms, potentially reversible conditions should be identified in the diagnostic evaluation of the patient.

Adolescent↗
PubMed1992

Validity of peak expiratory flow measurement in assessing reversibility of airflow obstruction.

BACKGROUND: Assessing the reversibility of airflow obstruction by peak expiratory (PEF) measurements would be practicable in general practice, but its usefulness has not been investigated. METHODS: PEF measurements were performed (miniWright peak flow meter) in 73 general practice patients (aged 40 to 84) with a history of asthma or chronic obstructive lung disease before and after 400 micrograms inhaled sulbutamol. The change in PEF was compared with the change in forced expiratory volume in one second (FEV1). Reversible airflow obstruction was analysed in two ways according to previous criteria. When defined as a 9% or greater increase in FEV1 expressed as a percentage of predicted values reversibility was observed in 42% of patients. Relative operating characteristic analysis showed that an absolute improvement in PEF of 60 l/min or more gave optimal discrimination between patients with reversible and irreversible airflow obstruction (the sensitivity and specificity of an increase of 60 l/min in detecting a 9% or more increase in FEV1 as a percentage of predicted values were 68% and 93% respectively, with a positive predictive value of 87%). When defined as an increase of 190 ml or more in FEV1, reversible airflow obstruction was observed in 53% of patients. Again an absolute improvement in PEF of 60 l/min or more gave optimal discrimination between patients with reversible and irreversible airflow obstruction (sensitivity 56%, specificity 94%, and positive predictive value 92%). CONCLUSION: Absolute changes in PEF can be used as a simple technique to diagnose reversible airflow obstruction in patients from general practice.

Adult↗
PubMed1987

Reversal of the exercise-induced increase in muscle permeability to glucose.

Exercise is associated with an increase in permeability of muscle to glucose that reverses slowly (h) in fasting rats during recovery. Previous studies showed that carbohydrate feeding speeds and carbohydrate restriction slows reversal of the exercise-induced increase in glucose uptake. This study was designed to evaluate the roles of glucose transport, glycogen synthesis, and protein synthesis in the reversal process in rat epitrochlearis muscle. In contrast to recovery in vivo, when muscles were incubated without insulin in vitro, the exercise-induced increase in muscle permeability to sugar reversed rapidly regardless of whether glucose transport or glycogen synthesis occurred. Inhibition of protein synthesis did not prevent the reversal. Addition of 33% rat serum or a low concentration of insulin to the incubation medium markedly slowed reversal in vitro. We conclude that 1) prolonged persistence of the increased permeability of mammalian muscle to glucose after exercise requires a low concentration of insulin, and 2) reversal of the increase in permeability does not require glucose transport, glycogen synthesis, or protein synthesis.

Animals↗
PubMed1981

Reversal of cholecystokinin-induced persistent stimulation of pancreatic enzyme secretion by dibutyryl cyclic GMP.

When pancreatic acini are first incubated with cholecystokinin, washed to remove free cholecystokinin, and then reincubated in fresh incubation solution, there is a significant residual stimulation of amylase secretion. Butyryl derivatives of cyclic GMP can prevent as well as reverse this cholecystokinin-induced residual stimulation. At 37 degrees C the nucleotide-induced reversal is complete within a few minutes, but at 4 degrees C complete reversal requires 90 min of incubation. The ability of butyryl cyclic GMP to reverse cholecystokinin-induced residual stimulation is itself fully reversible, and the nucleotide-induced reversal is accompanied by restoration of full responsiveness to cholecystokinin. The ability of dibutyryl cyclic GMP to reverse cholecystokinin-induced residual stimulation appears to result from the ability of the nucleotide to displace cholecystokinin from its receptors in pancreatic acini.

Amylases↗
PubMed1998

Menhaden oil prevents but does not reverse sucrose-induced insulin resistance in rats.

Although fish oil supplementation may prevent the onset of diet-induced insulin resistance in rats, it appears to worsen glycemic control in humans with existing insulin resistance. In the present study, the euglycemic, hyperinsulinemic (4x basal) clamp technique with [3-3H]glucose and 2-deoxy-[1-14C]glucose was used to directly compare the ability of fish oil to prevent and reverse sucrose-induced insulin resistance. In study 1 (prevention study), male Wistar rats were fed a purified high-starch diet (68% of total energy), high-sucrose diet (68% of total energy), or high-sucrose diet in which 6% of the fat content was replaced by menhaden oil for 5 wk. In study 2 (reversal study), animals were fed the high-starch or high-sucrose diets for 5 wk and then the sucrose animals were assigned to one of the following groups for an additional 5 wk: high starch, high sucrose, or high sucrose with 6% menhaden oil. Rats fed the high-starch diet for 10 wk served as controls. In study 3 (2nd reversal study), animals followed a similar diet protocol as in study 2; however, the reversal period was extended to 15 wk. In study 1, the presence of the fish oil in the high-sucrose diet prevented the development of insulin resistance. Glucose infusion rates (GIR, mg.kg-1.min-1) were 17.0 +/- 0.9 in starch, 10.6 +/- 1.7 in sucrose, and 15.1 +/- 1.5 in sucrose with fish oil animals. However, in study 2, this same diet was unable to reverse sucrose-induced insulin resistance (GIR, 16.7 +/- 1.4 in starch, 7.1 +/- 1.5 in sucrose, and 4.8 +/- 0.9 in sucrose with fish oil animals). Sucrose-induced insulin resistance was reversed in rats that were switched back to the starch diet (GIR, 18.6 +/- 3.0). Results from study 3 were similar to those observed in study 2. In summary, fish oil was effective in preventing diet-induced insulin resistance but not able to reverse it. A preexisting insulin-resistant environment interferes with the positive effects of menhaden oil on insulin action.

Animals↗
PubMed1994

Reversal of pulmonary capillary ischemia-reperfusion injury by rolipram, a cAMP phosphodiesterase inhibitor.

Isoproterenol (ISO) and forskolin, agents that increase adenosine 3',5'-cyclic monophosphate (cAMP) via adenylyl cyclase activation, reverse lung injury associated with increased microvascular permeability. We studied the role of rolipram, a relatively isozyme-selective cAMP phosphodiesterase (PDE) inhibitor, in reversing increased capillary permeability due to ischemia-reperfusion (I/R), a form of oxidant injury in the lung, by using the isolated perfused rat lung model. Rolipram (2 microM) administered after 45 min of ischemia and 45 min of reperfusion reduced I/R-increased permeability as measured by the capillary filtration coefficient to control lung values. Computer image analysis of air space edema and perivascular cuffing, as well as wet-to-dry weight ratios, confirms the permeability reversal by rolipram administration. Rolipram inhibition of cAMP PDE in the lung was assessed by using [3H]adenine prelabeling adapted for the whole lung and perfusate [3H]cAMP accumulation. Rolipram failed to increase perfusate cAMP alone but dramatically increased perfusate cAMP above ISO alone. Dose-response relationships of ISO or rolipram show a close correlation of the half-maximal effective dose (ED50) for injury reversal and perfusate cAMP production. The combination of rolipram and ISO produced synergistic reversal of I/R injury. We conclude that reversal of I/R-induced increased microvascular permeability can be achieved with rolipram and that the mechanism of action of rolipram is probably through PDE isozyme-selective inhibition. The similarity of the ED50 values for cAMP efflux and reversal of permeability increases also supports a close coupling between cAMP accumulation and endothelial cell permeability.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2003

Blockade of cyclic AMP-dependent protein kinase does not prevent the reverse ocular dominance shift in kitten visual cortex.

Monocular deprivation (MD) during the critical period for the development of visual cortex causes a loss of binocular response of neurons and a shift to the open eye, a normal ocular dominance (OD) shift. However, when MD is combined with chronic inactivation of the visual cortex by muscimol, the OD distribution of the neurons shifts to the deprived eye (reverse OD shift). We have previously shown that the normal OD shift is abolished by chronic infusion of the protein kinase A (PKA) inhibitor, 8-chloroadenosine-3', 5'-cyclic monophosphorothioate, Rp-isomer (Rp-8-Cl-cAMPS), into kitten visual cortex. In this study, we investigated the effect of this inhibitor on the reverse OD shift. Combination of MD and muscimol infusion into the visual cortex of 6-wk-old kittens caused a reverse OD shift that was comparable to that seen in previous studies. However, a reverse OD shift was also seen with concurrent infusion of the PKA inhibitor with muscimol. The strongest OD shift was observed in layer IV regardless of the presence or absence of the PKA inhibitor. This suggests that the dissociation of pre- and postsynaptic activities, which occurs mainly at thalamocortical synapses, induces the reverse OD shift and that inhibition of PKA does not prevent it. Presumably, an inhibition of PKA has no effect in silent cortex. We conclude that 1) an activation of PKA is not required for the induction of the reverse OD shift, and 2) the intracellular signaling mechanism underlying MD-induced OD plasticity differs between normal and reverse OD shifts.

Animals↗
PubMed1989

Reversal of atherosis and sclerosis. The two components of atherosclerosis.

In 1904, Marchand recognized the consistent association of fatty degeneration and vessel stiffening and introduced the term "atherosclerosis" to indicate this combination. Current research is focused principally on the lipid component, but there is evidence that both aspects are reversible. Atheromatous lipids add significantly to the volume of lesions and thus contribute to vascular obstruction and end-organ damage. Reversal of atherosis has been observed in all the major species used in atherosclerosis research; rabbits, swine, dogs, chicks, pigeons, and subhuman primates. Direct evidence for reversal in humans is based on angiographic trials and is less extensive. One femoral artery and one coronary artery trial indicate that the lesions can be stabilized. CLAS, the largest angiographic trial to date, indicates that coronary lesion reversal is possible. Clinical effects of sclerosis are more subtle, and there is little evidence that sclerosis alone leads to end-organ damage. However, it should be noted that atherosclerotic lesions producing end-organ damage invariably have a major fibrous component. Sclerotic vessels have reduced systolic expansion and abnormally rapid pulse wave propagation, which can be measured noninvasively. Primate studies indicate that sclerosis is induced by hypercholesterolemic diets and is reversible when these diets are withdrawn. Changes in sclerosis may be another useful indicator of the formation and reversal of lesions and may involve changes in EDRF. Future studies of atherosclerosis reversal should use a combination of measures to evaluate both atherosis and sclerosis.

Angiography↗
PubMed1993

Thallium reinjection demonstrates viable myocardium in regions with reverse redistribution.

BACKGROUND: The clinical significance and pathophysiological mechanisms of reverse redistribution on stress-redistribution thallium-201 myocardial scintigraphy in patients with chronic coronary artery disease are unclear. Recent studies have shown that thallium-201 reinjection is a useful technique for the detection of myocardial viability in chronic coronary artery disease. In this investigation we determined whether thallium reinjection distinguishes viable from nonviable myocardium in regions with reverse redistribution. METHODS AND RESULTS: We studied 39 patients with chronic stable coronary artery disease (age, 60 +/- 10 years), all of whom demonstrated reverse redistribution on standard exercise-redistribution thallium single-photon emission computed tomography (SPECT). Reverse redistribution was defined as > or = 10% decrease in relative thallium-201 activity between stress and redistribution images and included either the worsening of a perfusion defect apparent on post-stress images or the appearance of a new defect on the redistribution images. Thallium reinjection was performed immediately after the 3- to 4-hour redistribution study. Of 39 regions with reverse redistribution, 32 (82%) showed enhanced thallium-201 activity (> or = 10% increase) after reinjection. In the other 7 regions (18%), the scintigraphic defect persisted after reinjection. Abnormal Q waves were present in only 8 of 32 (25%) regions with enhanced thallium-201 uptake after reinjection compared with 5 of 7 (71%) regions not responding to reinjection (P < .05). Akinetic or dyskinetic wall motion was present in 3 of 32 (9%) regions showing enhanced uptake after reinjection, in contrast with 5 of 7 (71%) regions not responding to reinjection (P < .01). Critically stenosed or totally occluded coronary arteries supplied 24 of 29 (83%) regions with enhanced thallium-201 uptake after reinjection but only 2 of 7 (28%) regions not showing a positive response to reinjection (P < .05). Collateral circulation was detected in 23 of 29 (79%) regions with a positive thallium reinjection effect but in only 1 of the other 7 regions (P < .01). Sixteen of the 39 patients also underwent positron emission tomography using 18F-fluorodeoxyglucose (FDG) to assess glucose utilization and H2(15)O to assess regional blood flow. The 14 regions with reverse redistribution that responded to reinjection with enhanced thallium uptake all showed either normal patterns of FDG uptake and flow or an ischemic pattern with increased FDG uptake relative to flow. Reduced FDG uptake and reduced flow values were seen in the two regions not responding to thallium reinjection. CONCLUSIONS: These observations indicate that reverse redistribution in chronic coronary artery disease usually reflects viable myocardium, critically dependent upon collateral circulation.

Cardiac Catheterization↗
PubMed1997

Low efficiency of Ca2+ entry through the Na(+)-Ca2+ exchanger as trigger for Ca2+ release from the sarcoplasmic reticulum. A comparison between L-type Ca2+ current and reverse-mode Na(+)-Ca2+ exchange.

It has been proposed that Ca2+ entry through the Na(+)-Ca2+ exchanger can contribute significantly to the trigger for Ca2+ release from the sarcoplasmic reticulum (SR). We have compared the characteristics of Ca2+ release triggered by reverse-mode Na(+)-Ca2+ exchange and by L-type Ca2+ current (ICaL) during depolarizing steps in single guinea pig ventricular myocytes (whole-cell voltage clamp, fluo 3 and fura-red as [Ca2+]i indicators, 36 +/- 1 degrees C, K(+)-based pipette solution with 20 mmol/L [Na+]). Conditioning pulses to +60 mV ensured comparable Ca2+ loading of the SR. In the presence of ICaL, [Ca2+]i transients typically have an early and rapid rising phase reflecting Ca2+ release, which has a bell-shaped voltage dependence with a peak at +10 mV. With Ca2+ entry through Na(+)-Ca2+ exchange only (20 mumol/L nisoldipine), Ca2+ release flux from the SR is decreased and directly related to the amplitude of the depolarizing step. Ca2+ release is preceded by a significant delay (81 +/- 21 ms at +20 mV, 24 +/- 4 ms at +70 mV) related to Ca2+ entry through the exchanger. Triggered release interrupts Ca2+ entry, as evidenced by reversal of the exchanger current. At potentials positive to +40 mV, Ca2+ influx through Na(+)-Ca2+ exchange, calculated from the outward exchange current, reaches magnitudes comparable to ICaL, but Ca2+ release due to reverse-mode Na(+)-Ca2+ exchange still has a significant delay. We calculated trigger efficiency as the ratio between the maximal rate of Ca2+ release and the Ca2+ influx preceding this release; efficiency of reverse-mode Na(+)-Ca2+ exchange is approximately four times less than that of ICaL. With both ICaL and reverse-mode Na(+)-Ca2+ exchange present, Ca2+ release is triggered by ICaL, and a contribution of reverse-mode Na(+)-Ca2+ exchange to the trigger could not be detected at potentials below +60 mV. These characteristics of reverse-mode Na(+)-Ca2+ exchange predict that its role as a trigger for Ca2+ release during the action potential is likely to be negligible.

Animals↗
PubMed2004

More accurate identification of reversible ischemic injury in human stroke by cerebrospinal fluid suppressed diffusion-weighted imaging.

BACKGROUND AND PURPOSE: The apparent diffusion coefficient (ADC) derived from diffusion-weighted (DWI) MRI has been used to differentiate reversible from irreversible ischemic injury. However, the ADC can be falsely elevated by partial volume averaging of cerebrospinal fluid (CSF) with parenchyma, limiting the accuracy of this approach. This study tested the hypothesis that the accuracy of differentiating reversible from irreversible ischemic injury could be improved by CSF suppression at image acquisition. METHODS: Sixteen patients presenting within 6 hours from symptoms, and having partial reversal of the acute lesion on DWI were studied using conventional CSF-suppressed DWI. Lesions were segmented from coregistered acute DWI and follow-up fluid-attenuated inversion recovery (FLAIR) series. The segmented volumes were applied to conventional (ADC(C)) and CSF-suppressed ADC (ADC(FLIPD)) maps to classify each voxel as progressed to infarct or reversed. Individual voxel ADC values were pooled across all patients. Sensitivity to predict reversal, specificity, and accuracy were calculated for both methods. RESULTS: A total of 25 313 voxels were classified as progressed and 31 952 voxels reversed. Across all lesion voxels, ADC(FLIPD) values more accurately depicted tissue fate compared with ADC(C) values (P<0.0001). The largest difference in the two methods was in voxels with <75% parenchyma, where the accuracy of ADC(C) was only 50% compared with 62% for ADC(FLIPD.) CONCLUSIONS: CSF-suppressed ADC measurements gave a more accurate identification of reversible ischemic injury in this sample. We predict that multimodal MRI models of tissue viability in ischemic stroke will be more accurate if CSF-suppressed ADC measurements are used.

Adult↗