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Gestational trophoblastic disease (GTD) forms a heterogeneous group of interrelated lesions which are characterized by an abnormal proliferation of the different types of trophoblastic epithelium. Complete hydatidiform moles represent a noninvasive placental disease that is characterized by hydropic swelling of the chorionic villi with marked trophoblastic proliferation. The partial mole contains two populations of villi: one of normal size, the other hydropic with less marked trophoblastic hyperplasia. The risk of developing persistent GTD is very low. Choriocarcinomas represent an avillous invasive proliferation of trophoblastic cells surrounded by necroses and hemorrhages displaying a dimorphic pattern with early vascular invasion and hematogeneous metastatic spread. Placental site trophoblastic tumor (PSTT) resembles the rarest form of GTD. In its cellular composition, PSTT preferentially contains intermediate trophoblastic cells with typically positive hPL-immunostaining. Mostly, PSTT's are benign tumors, but malignant cases are well known. Miscelleanous forms of GTD include the exaggerated placental site and the placental site nodule or plaque. Both lesions are proliferations of the intermediate trophoblast. Staging of GTD should only be applied in cases of persistent disease. All different staging systems, including the revised FIGO system, the classification of the National Institute of Health (NIH), the WHO scoring system and the currently adopted TNM-system are able to define high risk patients.
Gen Diagn Pathol 1997 Nov
PMID:Histologic classification and staging of gestational trophoblastic disease. 944 66

Voltage-gated potassium (K+) channels are multi-ion pores. Recent studies suggest that, similar to calcium channels, competition between ionic species for intrapore binding sites may contribute to ionic selectivity in at least some K+ channels. Molecular studies suggest that a putative constricted region of the pore, which is presumably the site of selectivity, may be as short as one ionic diameter in length. Taken together, these results suggest that selectivity may occur at just a single binding site in the pore. We are studying a chimeric K+ channel that is highly selective for K+ over Na+ in physiological solutions, but conducts Na+ in the absence of K+. Na+ and K+ currents both display slow (C-type) inactivation, but had markedly different inactivation and deactivation kinetics; Na+ currents inactivated more rapidly and deactivated more slowly than K+ currents. Currents carried by 160 mM Na+ were inhibited by external K+ with an apparent IC50 <30 microM. K+ also altered both inactivation and deactivation kinetics of Na+ currents at these low concentrations. In the complementary experiment, currents carried by 3 mM K+ were inhibited by external Na+, with an apparent IC50 of approximately 100 mM. In contrast to the effects of low [K+] on Na+ current kinetics, Na+ did not affect K+ current kinetics, even at concentrations that inhibited K+ currents by 40-50%. These data suggest that Na+ block of K+ currents did not involve displacement of K+ from the high affinity site involved in gating kinetics. We present a model that describes the permeation pathway as a single high affinity, cation-selective binding site, flanked by low affinity, nonselective sites. This model quantitatively predicts the anomalous mole fraction behavior observed in two different K+ channels, differential K+ and Na+ conductance, and the concentration dependence of K+ block of Na+ currents and Na+ block of K+ currents. Based on our results, we hypothesize that the permeation pathway contains a single high affinity binding site, where selectivity and ionic modulation of gating occur.
J Gen Physiol 1998 Feb
PMID:The interaction of Na+ and K+ in voltage-gated potassium channels. Evidence for cation binding sites of different affinity. 945 Sep 39

A distinctive feature of the voltage-dependent chloride channels ClC-0 (the Torpedo electroplaque chloride channel) and ClC-1 (the major skeletal muscle chloride channel) is that chloride acts as a ligand to its own channel, regulating channel opening and so controlling the permeation of its own species. We have now studied the permeation of a number of foreign anions through ClC-1 using voltage-clamp techniques on Xenopus oocytes and Sf9 cells expressing human (hClC-1) or rat (rClC-1) isoforms, respectively. From their effect on channel gating, the anions presented in this paper can be divided into three groups: impermeant or poorly permeant anions that can not replace Cl- as a channel opener and do not block the channel appreciably (glutamate, gluconate, HCO3-, BrO3-); impermeant anions that can open the channel and show significant block (methanesulfonate, cyclamate); and permeant anions that replace Cl- at the regulatory binding site but impair Cl- passage through the channel pore (Br-, NO3-, ClO3-, I-, ClO4-, SCN-). The permeability sequence for rClC-1, SCN- approximately ClO4- > Cl- > Br- > NO3- approximately ClO3- > I- >> BrO3- > HCO3- >> methanesulfonate approximately cyclamate approximately glutamate, was different from the sequence determined for blocking potency and ability to shift the Popen curve, SCN- approximately ClO4- > I- > NO3- approximately ClO3- approximately methanesulfonate > Br- > cyclamate > BrO3- > HCO3- > glutamate, implying that the regulatory binding site that opens the channel is different from the selectivity center and situated closer to the external side. Channel block by foreign anions is voltage dependent and can be entirely accounted for by reduction in single channel conductance. Minimum pore diameter was estimated to be approximately 4.5 A. Anomalous mole-fraction effects found for permeability ratios and conductance in mixtures of Cl- and SCN- or ClO4- suggest a multi-ion pore. Hydrophobic interactions with the wall of the channel pore may explain discrepancies between the measured permeabilities of some anions and their size.
J Gen Physiol 1998 May
PMID:Permeation and block of the skeletal muscle chloride channel, ClC-1, by foreign anions. 956 3

Ca(2+)-activated Cl channels (Cl(Ca)Cs) are an important class of anion channels that are opened by increases in cytosolic [Ca(2+)]. Here, we examine the mechanisms of anion permeation through Cl(Ca)Cs from Xenopus oocytes in excised inside-out and outside-out patches. Cl(Ca)Cs exhibited moderate selectivity for Cl over Na: P(Na)/P(Cl) = 0.1. The apparent affinity of Cl(Ca)Cs for Cl was low: K(d) = 73 mM. The channel had an estimated pore diameter >0.6 nm. The relative permeabilities measured under bi-ionic conditions by changes in E(rev) were as follows: C(CN)(3) > SCN > N(CN)(2) > ClO(4) > I > N(3) > Br > Cl > formate > HCO(3) > acetate = F > gluconate. The conductance sequence was as follows: N(3) > Br > Cl > N(CN)(2) > I > SCN > COOH > ClO(4) > acetate > HCO(3) = C(CN)(3) > gluconate. Permeant anions block in a voltage-dependent manner with the following affinities: C(CN)(3) > SCN = ClO(4) > N(CN)(2) > I > N(3) > Br > HCO(3) > Cl > gluconate > formate > acetate. Although these data suggest that anionic selectivity is determined by ionic hydration energy, other factors contribute, because the energy barrier for permeation is exponentially related to anion hydration energy. Cl(Ca)Cs exhibit weak anomalous mole fraction behavior, implying that the channel may be a multi-ion pore, but that ions interact weakly in the pore. The affinity of the channel for Ca(2+) depended on the permeant anion at low [Ca(2+)] (100-500 nM). Apparently, occupancy of the pore by a permeant anion increased the affinity of the channel for Ca(2+). The current was strongly dependent on pH. Increasing pH on the cytoplasmic side decreased the inward current, whereas increasing pH on the external side decreased the outward current. In both cases, the apparent pKa was voltage-dependent with apparent pKa at 0 mV = approximately 9.2. The channel may be blocked by OH(-) ions, or protons may titrate a site in the pore necessary for ion permeation. These data demonstrate that the permeation properties of Cl(Ca)Cs are different from those of CFTR or ClC-1, and provide insights into the nature of the Cl(Ca)C pore.
J Gen Physiol 2000 Dec
PMID:Anion permeation in Ca(2+)-activated Cl(-) channels. 1109 50

The molar extinction of rhodopsin is 40,600 cm.(2) per mole equivalent of retinene; i.e., this is the extinction of a solution of rhodopsin which is produced by, or yields on bleaching, a molar solution of retinene. The molar extinctions of all-trans retinene and all-trans retinene oxime have also been determined in ethyl alcohol and aqueous digitonin solutions. On the assumption that each chromophoric group of rhodopsin is made from a single molecule of retinene, it is concluded that the primary photochemical conversion of rhodopsin to lumi-rhodopsin has a quantum efficiency of 1; though the over-all bleaching of rhodopsin in solution to retinene and opsin may have a quantum efficiency as low as one-half. On bleaching cattle rhodopsin, about two sulfhydryl groups appear for each molecule of retinene liberated. In frog rhodopsin the -SH:retinene ratio appears to be higher, 5:2 or perhaps even 3:1. Some of this sulfhydryl appears to have been engaged in binding retinene to opsin; some may have been exposed as the result of changes in opsin which accompany bleaching, comparable with protein denaturation.
J Gen Physiol 1953 Nov 20
PMID:The molar extinction of rhodopsin. 1310 55

The sedimentation behavior of aqueous solutions of digitonin and of cattle rhodopsin in digitonin has been examined in the ultracentrifuge. In confirmation of earlier work, digitonin was found to sediment as a micelle (D-1) with an s(20) of about 6.35 Svedberg units, and containing at least 60 molecules. The rhodopsin solutions sediment as a stoichiometric complex of rhodopsin with digitonin (RD-1) with an s(20) of about 9.77 Svedberg units. The s(20) of the RD-1 micelle is constant between pH 6.3 and 9.6, and in the presence of excess digitonin. RD-1 travels as a single boundary also in the electrophoresis apparatus at pH 8.5, and on filter paper at pH 8.0. The molecular weight of the RD-1 micelle lies between 260,000 and 290,000. Of this, only about 40,000 gm. are due to rhodopsin; the rest is digitonin (180 to 200 moles). Comparison of the relative concentrations of RD-1 and retinene in solutions of rhodopsin-digitonin shows that RD-1 contains only one retinene equivalent. It can therefore contain only one molecule of rhodopsin with a molecular weight of about 40,000. Cattle rhodopsin therefore contains only one chromophore consisting of a single molecule of retinene. It is likely that frog rhodopsin has a similar molecular weight and also contains only one chromophore per molecule. The molar extinction coefficient of rhodopsin is therefore identical with the extinction coefficient per mole of retinene (40,600 cm.(2) per mole) and the E(1 per cent, 1 cm., 500 mmicro) has a value of about 10. Rhodopsin constitutes about 14 per cent of the dry weight, and 3.7 per cent of the wet weight of cattle outer limbs. This corresponds to about 4.2 x 10(6) molecules of rhodopsin per outer limb. The rhodopsin content of frog outer limbs is considerably higher: about 35 per cent of the dry weight, and 10 per cent of the wet weight, corresponding to about 2.1 x 10(9) molecules per outer limb. Thus the frog outer limb contains about five hundred times as much rhodopsin as the cattle outer limb. But the relative volumes of these structures are such that the ratio of concentrations is only about 2.5 to 1 on a weight basis. Rhodopsin accounts for at least one-fifth of the total protein of the cattle outer limb; for the frog, this value must be higher. The extinction (K(500)) along its axis is about 0.037 cm.(2) for the cattle outer limb, and about 0.50 cm.(2) for the frog outer limb.
J Gen Physiol 1954 Jan 20
PMID:The molecular weight of rhodopsin and the nature of the rhodopsin-digitonin complex. 1311 8

1. The enzyme which splits threonine to acetaldehyde and glycine has been partially purified from rat liver (five- to sixfold purification) and the name threonine aldolase proposed for it. 2. The general properties of threonine aldolase have been studied. The enzyme is unstable to a pH below 5. The pH optimum of the enzyme reaction is at 7.5-7.7. The initial rate of production of acetaldehyde is proportional to the enzyme concentration, and when the enzyme concentration is constant, the production of acetaldehyde is proportional to the time, provided that the substrate is in excess. The enzyme is inhibited by the carbonyl group reagent, hydroxylamine. Attempts to demonstrate that pyridoxal phosphate is a cofactor were unsuccessful. 3. The enzyme splits only L-allothreonine and L-threonine and is inactive against the D-forms of these amino acids. 4. The enzyme reaction on DL-allothreonine follows first order kinetics. From the first order velocity constants and the initial rates of the rates of the reaction at various substrate concentrations the Michaelis constant, Ks, for this substrate has been evaluated. Michaelis constants have also been determined for threonine. 5. The optimum temperature for the enzymatic breakdown of DL-allothreonine at pH 7.65 was found to be 50 degrees C. in phosphate buffer and 48 degrees C. in tris-maleate buffer. The rate of thermal inactivation of the enzyme threonine aldolase obeys a first order reaction. The heat of thermal inactivation was calculated by the aid of the van't Hoff-Arrhenius equation to be 43,000 cal. per mole for the temperature range 41.2-46.6 degrees C. 6. Equivalent amounts of acetaldehyde and glycine were formed from DL-allothreonine and the enzymatic breakdown of DL-allothreonine was found to be irreversible.
J Gen Physiol 1954 Nov 20
PMID:Enzymatic breakdown of threonine by threonine aldolase. 1321 95

Preparation of Reversibly Inactivated (R.I.) Phage.- If B. megatherium phage (of any type, or in any stage of purification) is suspended in dilute salt solutions at pH 5-6, it is completely inactivated; i.e., it does not form plaques, or give rise to more phage when mixed with a sensitive organism (Northrop, 1954). The inactivation occurs when the phage is added to the dilute salt solution. If a suspension of the inactive phage in pH 7 peptone is titrated to pH 5 and allowed to stand, the activity gradually returns. The inactivation is therefore reversible. Properties of R.I. Phage.- The R.I. phage is adsorbed by sensitive cells at about the same rate as the active phage. It kills the cells, but no active phage is produced. The R.I. phage therefore has the properties of phage "ghosts" (Herriott, 1951) or of colicines (Gratia, 1925), or phage inactivated by ultraviolet light (Luria, 1947). The R.I. phage is sedimented in the centrifuge at the same rate as active phage. It is therefore about the same size as the active phage. The R.I. phage is most stable in pH 7, 5 per cent peptone, and may be kept in this solution for weeks at 0 degrees C. The rate of digestion of R.I. phage by trypsin, chymotrypsin, or desoxyribonuclease is about the same as that of active phage (Northrop, 1955 a). Effect of Various Substances on the Formation of R.I. Phage.- There is an equilibrium between R.I. phage and active phage. The R.I. form is the stable one in dilute salt solution, pH 5 to 6.5 and at low temperature (<20 degrees C.). At pH >6.5, in dilute salt solution, the R.I. phage changes to the active form. The cycle, active right harpoon over left harpoon inactive phage, may be repeated many times at 0 degrees C. by changing the pH of the solution back and forth between pH 7 and pH 6. Irreversible inactivation is caused by distilled water, some heavy metals, concentrated urea or quanidine solutions, and by l-arginine. Reversible inactivation is prevented by all salts tested (except those causing irreversible inactivation, above). The concentration required to prevent R.I. is lower, the higher the valency of either the anion or cation. There are great differences, however, between salts of the same valency, so that the chemical nature as well as the valency is important. Peptone, urea, and the amino acids, tryptophan, leucine, isoleucine, methionine, asparagine, dl-cystine, valine, and phenylalanine, stabilize the system at pH 7, so that no change occurs if a mixture of R.I. and active phage is added to such solutions. The active phage remains active and the R.I. phage remains inactive. The R.I. phage in pH 7 peptone becomes active if the pH is changed to 5.0. This does not occur in solutions of urea or the amino acids which stabilize at pH 7.0. Kinetics of Reversible Inactivation.- The inactivation is too rapid, even at 0 degrees to allow the determination of an accurate time-inactivation curve. The rate is independent of the phage concentration and is complete in a few seconds, even in very dilute suspensions containing <1 x 10(4) particles/ml. This result rules out any type of bimolecular reaction, or any precipitation or agglutination mechanism, since the minimum theoretical time for precipitation (or agglutination) of a suspension of particles in a concentration of only 1 x 10(4) per ml. would be about 300 days even though every collision were effective. Mechanism of Salt Reactivation.- Addition of varying concentrations of MgSO(4) (or many other salts) to a suspension of either active or R.I. phage in 0.01 M, pH 6 acetate buffer results in the establishment of an equilibrium ratio for active/R.I. phage. The higher the concentration of salt, the larger proportion of the phage is active. The results, with MgSO(4), are in quantitative agreement with the following reaction: See PDF for Equation Effect of Temperature.- The rate of inactivation is too rapid to be measured with any accuracy, even at 0 degrees C. The rate of reactivation in pH 5 peptone, at 0 and 10 degrees , was measured and found to have a temperature coefficient Q(10) = 1.5 corresponding to a value of E (Arrhenius' constant) of 6500 cal. mole(-1). This agrees very well with the temperature coefficient for the reactivation of denatured soy bean trypsin inhibitor (Kunitz, 1948). The equilibrium between R.I. and active phage is shifted toward the active side by lowering the temperature. The ratio R.I.P./AP is 4.7 at 15 degrees and 2.8 at 2 degrees . This corresponds to a change in free energy of -600 cal. mole(-1) and a heat of reaction of 11,000. These values are much lower than the comparative one for trypsin (Anson and Mirsky, 1934 a) or soy bean trypsin inhibitor (Kunitz, 1948). Neither the inactivation nor the reactivation reactions are affected by light. The results in general indicate that there is an equilibrium between active and R.I. phage. The R.I. phage is probably an intermediate step in the formation of inactive phage. The equilibrium is shifted to the active side by lowering the temperature, adjusting the pH to 7-8 (except in the presence of high concentrations of peptone), raising the salt concentration, or increasing the valency of the ions present. The reaction may be represented by the following: See PDF for Equation The assumption that the active/R.I. phage equilibrium represents an example of native/denatured protein equilibrium predicts all the results qualitatively. Quantitatively, however, it fails to predict the relative rate of digestion of the two forms by trypsin or chymotrypsin, and also the effect of temperature on the equilibrium.
J Gen Physiol 1955 Nov 20
PMID:Inactivation and reactivation of B. megatherium phage. 1327 23

1. Addition of 2 moles of mersalyl, mercuric chloride, p-chloromercuribenzoate (PCMB), or methyl mercury hydroxide per mole of hemoglobin greatly reduces heme-heme interactions (n), yet these substances have quite different effects on the oxygen affinity (-log p(50)). Mersalyl and mercuric chloride at this concentration each increase the oxygen affinity, while PCMB and methyl mercury have little or no effect on the oxygen affinity. These effects are primarily associated with the binding of -SH groups, and are largely reversed on the addition of glutathione. -SH groups do not appear to be responsible for the Bohr effect. 2. Evidence is presented for the belief that the two hemes of each half-molecule of horse hemoglobin are situated on either side of a cluster of-SH groups. 3. The mechanism of interaction between the hemes is discussed. It is concluded that the reorganization of the protein architecture which accompanies oxygenation plays a central role in this interaction, in agreement with the views of Pauling and Wyman.
J Gen Physiol 1956 Mar 20
PMID:Sulfhydryl groups and the structure of hemoglobin. 1329 56

Purified preparations of cattle rhodopsin have been titrated to various pH, irradiated, and the pH changes followed thereafter until completed. In this way we have obtained the titration curves of rhodopsin, of the immediate product of irradiation, measured within 30 seconds; and of the final product of irradiation (opsin). The rhodopsin preparations display about 54 titratable groups per mole of pigment: about 34 base-binding and 20 acid-binding groups. In default of an absolute purification, one cannot be sure that all of these go with rhodopsin itself. Exposure to light induces an immediate rise of pH between pH 2 and 8, maximal at about pH 5. This-followed by its slow partial or complete reversal-is the only change of pH in the physiological range (6-7). It involves the exposure of 1 new acid-binding group per mole of rhodopsin with pK about 6.6, close therefore to that of the imidazole group of histidine. At acid and alkaline pH this immediate change is followed by slower changes, occupying up to 40 minutes at 20 degrees C. These changes are always in the direction of neutrality. They involve increases of 5 to 6 moles acid bound at acid pH, and 7 moles base bound at alkaline pH. They are associated with the irreversible denaturation of opsin in acid and alkaline solution, as evidenced by loss of its capacity to regenerate rhodopsin. Such frank denaturation procedures as the exposure of rhodopsin to alkali or heat in the dark result in comparable acid-base changes.
J Gen Physiol 1956 Jul 20
PMID:Acid-base properties of rhodopsin and opsin. 1334 44


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