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C L Henry

Publications and source records attributed to C L Henry.

14 recordsLinked to original sources
PubMed2001

Channel activity of deamidated isoforms of prion protein fragment 106-126 in planar lipid bilayers.

Using the lipid bilayer technique, we have found that age-related derivatives, PrP[106-126] (L-Asp108) and PrP[106-126] (L-iso-Asp108), of the prion protein fragment 106-126 (PrP[106-126] (Asn108)) form heterogeneous ion channels. The deamidated isoforms, PrP[106-126] (L-Asp108) and PrP[106-126] (L-iso-Asp108), showed no enhanced propensity to form heterogeneous channels compared with PrP[106-126] (Asn108). One of the PrP[106-126] (L-Asp108)- and PrP[106-126] (L-iso-Asp108)-formed channels had three kinetic modes. The current-voltage (I-V) relationship of this channel, which had a reversal potential, E(rev), between -40 and -10 mV close to the equilibrium potential for K+ (E(K)-35 mV), exhibited a sigmoidal shape. The value of the maximal slope conductance (g(max)) was 62.5 pS at positive potentials between 0 and 140 mV. The probability (P(o)) and the frequency (F(o)) of the channel being open had inverted and bell-shaped curves, respectively, with a peak at membrane potential (V(m)) between -80 and +80 mV. The mean open and closed times (T(o) and T(c)) had inverted bell-shaped curves. The biophysical properties of PrP[106-126] (L-Asp108)- and PrP[106-126] (L-iso-Asp108)-formed channels and their response to Cu(2+) were similar to those of channels formed with PrP[106-126] (Asn108). Cu(2+) shifted the kinetics of the channel from being in the open state to a "burst state" in which rapid channel activities were separated by long durations of inactivity. The action of Cu(2+) on the open channel activity was both time-dependent and voltage-dependent. The fact that Cu(2+) induced changes in the kinetics of this channel with no changes in the conductance of the channel indicated that Cu(2+) binds at the mouth of the channel. Consistently with the hydrophilic and structural properties of PrP[106-126], the Cu(2+)-induced changes in the kinetic parameters of this channel suggest that the Cu(2+) binding site could be located at M(109) and H(111) of this prion fragment.

Action Potentials↗
PubMed2001

Diversity of amyloid beta protein fragment [1-40]-formed channels.

1. The lipid bilayer technique was used to characterize the biophysical and pharmacological properties of several ion channels formed by incorporating amyloid beta protein fragment (AbetaP) 1-40 into lipid membranes. Based on the conductance, kinetics, selectivity, and pharmacological properties, the following AbetaP[1-40]-formed ion channels have been identified: (i) The AbetaP[1-40]-formed "bursting" fast cation channel was characterized by (a) a single channel conductance of 63 pS (250/50 mM KCl cis/trans) at +140 mV. 17 pS (250/50 mM KCl cis/trans) at -160 mV, and the nonlinear current-voltage relationship drawn to a third-order polynomial, (b) selectivity sequence PK > PNa > PLi = 1.0:0.60:0.47, (c) Po of 0.22 at 0 mV and 0.55 at +120 mV, and (d) Zn2+-induced reduction in current amplitude, a typical property of a slow block mechanism. (ii) The AbetaP[1-40]-formed "spiky" fast cation channel was characterized by (a) a similar kinetics to the "bursting" fast channel with exception for the absence of the long intraburst closures, (b) single channel conductance of 63 pS (250/50 KCl) at +140 mV 17 pS (250/50 KCl) at -160 mV, the current-voltage relationship nonlinear drawn to a third-order polynomial fit, and (c) selectivity sequence PRb > (iii) The AbetaP[1-40]-formed medium conductance channel was charcterized by (a) 275 pS (250/50 mM KCl cis/trans) at +140 mV and 19 pS (250/50 mM KCl cis/trans) at -160 mV and (b) inactivation at Vms more negative than -120 and more positive than +120 mV. (iv) The AbetaP[1-40]-formed inactivating large conductance channel was characterized by (a) fast and slow modes of opening to seven multilevel conductances ranging between 0-589 pS (in 250/50 mM KCI) at +140 mV and 0-704 pS (in 250/50 mM KCl) at -160 mV. (b) The fast mode which had a conductance of <250 pS was voltage dependent. The inactivation was described by a bell-shaped curve with a peak lag time of 7.2 s at +36 mV. The slow mode which had a conductance of >250 pS was also voltage dependent. The inactivation was described by a bell-shaped curve with a peak lag time of 7.0 s at -76 mV, (c) the value of PK/Pcholine for the fast mode was 3.9 and selectivity sequence PK > PCs > PNa > PLi = 1.0:0.94:0.87:0.59. The value of PK/Pcholine for the slow mode was 2.7 and selectivity sequence PK > FNa > PLi > PCs = 1.0:0.59:0.49:0.21, and (d) asymmetric blockade with 10 mM Zn2+-induced reduction in the large conductance state of the slow mode mediated via slow block mechanism. The fast mode of the large conductance channel was not affected by 10 mM Zn2+. 2. It has been suggested that, although the "bursting" fast channel, the "spiky" fast channel and the inactivating medium conductance channel are distinct, it is possible that they are intermediate configurations of yet another configuration underlying the inactivating large conductance channel. It is proposed that this heterogeneity is one of the most common features of these positively-charged cytotoxic amyloid-formed channels reflecting these channels ability to modify multiple cellular functions. 3. Furthermore, the formation of beta-sheet based oligomers could be an important common step in the formation of cytotoxic amyloid channels.

Alzheimer Disease↗
PubMed2001

Protein aggregation and deposition: implications for ion channel formation and membrane damage.

Protein deposition, aggregation, and formation of amyloids are associated with a wide range of pathologies, including several neurodegenerative diseases. Aggregation and deposition are a result of malfunction in protein folding, assembly, and transport, caused by protein mutation and/or changes in the cell environment. The mechanism of protein deposition and aggregation is triggered when the hydrophobic and positively charged regions of the misfolded proteins are exposed. The cells aim to regulate these misfolded and malfunctioning aggregation-prone proteins by degradation mechanisms, e.g., proteosomes, and/or by storing them in specialized compartments, e.g., Russell bodies and aggresomes. During these processes, however, some aggregation-prone protein intermediates are capable of aggregation and forming beta-sheet based channels in various negatively charged cellular membranes. Adverse cellular conditions, transitional metals, cellular proteins, and genetic mutations play an important role in the formation and function of these non-intrinsic channels. These channels, which can damage membrane function, are pathologic because they can disrupt the metabolic, ionic, and water homeostasis and distort signal transduction. We propose that different conformations of aggregation-prone proteins could alter cell regulation by modifying several ion transport systems and also by forming heterogeneous ion channels. The changes in membrane transport systems are proposed as early steps in impairing neuronal function preceding fibril formation. We conclude that these changes damage the membrane by compromising its integrity and increasing its ion permeability. This mechanism of membrane damage is a general mechanism that may explain other malfunctioning protein processing-related pathologies.

Alzheimer Disease↗
PubMed2001

Properties and modulation of alpha human atrial natriuretic peptide (alpha-hANP)-formed ion channels.

Using the lipid bilayer technique we have optimized recording conditions and confirmed that alpha human atrial natriuretic peptide [alpha-hANP(1-28)] forms single ion channels. The single channel currents recorded in 250/50 mM KCl cis/trans chambers show that the ANP-formed channels were heterogeneous, and differed in their conductance, kinetic, and pharmacological properties. The ANP-formed single channels were grouped as: (i) H202- and Ba2+-sensitive channel with fast kinetics; the nonlinear current-voltage (I-V) relationship of this channel had a reversal potential (Erev) of -28.2 mV, which is close to the equilibrium potential for K+ (EK = -35 mV) and a maximal slope conductance (gmax) of 68 pS at positive potentials. Sequential ionic substitution (KCl, K gluconate and choline Cl) of the cis solution suggests that the current was carried by cations. The fast channel had three modes (spike mode, burst mode, and open mode) that differed in their kinetics but not in their conductance properties. (ii) A large conductance channel possessing several subconductance levels that showed time-dependent inactivation at positive and negative membrane potentials (Vm). The inactivation ratio of the current at the end of the voltage step (Iss) to the initial current (Ii) activated immediately after the voltage step, (Iss/Ii), was voltage dependent and described by a bell-shaped curve. The maximal current-voltage (I-V) relationship of this channel, which had an Erev of +17.2 mV, was nonlinear and the value of gmax was 273 pS at negative voltages. (iii) A transiently-activated channel: the nonlinear I-V relationship of this channel had an Erev of -29.8 mV and the value of gmax was 160 pS at positive voltages. We propose that the voltage-dependence of the ionic currents and the kinetic parameters of these channel types indicate that if they were formed in vivo and activated by cytosolic factors they could change the membrane potential and the electrolyte homeostasis of the cell.

Amino Acid Sequence↗
PubMed1998

Discovery of ascomycin analogs with potent topical but weak systemic activity for treatment of inflammatory skin diseases.

Drug therapy for the major inflammatory skin diseases, which include atopic dermatitis, psoriasis and allergic contact dermatitis, is often inadequate due to poor efficacy, toxicity, or both. Much research has focused on the macrolactam T cell inhibitors as a promising new class of agents for immunotherapy, and medicinal chemistry efforts to design novel ascomycin analogs have produced clinically promising agents. A synthetic program to modify the ascomycin nucleus to alter its physicochemical properties and promote systemic clearance is described. A biologic screening strategy to identify analogs with reduced systemic activity and rapid pharmacokinetic elimination led to identification of the clinical candidate, ABT-281. A swine contact hypersensitivity model was used as a stringent indicator of skin penetration as human doses of topical corticosteroids produced inhibition only in the 50% range and ED50 values were 100-fold less potent than in rat. Also, cyclosporine was confirmed to be topically inactive in swine, as seen in human. ABT-281 had topical potency equal to tacrolimus (FK506) despite a severalfold lower potency for inhibiting swine T cells in vitro, consistent with superior skin penetration. ABT-281 was found to have a shorter duration of action after i.v. dosing in monkeys using an ex vivo whole blood IL-2 production assay. Systemic potency was reduced by 30-fold or more in rat popliteal lymph node hyperplasia and contact hypersensitivity assays. Following i.v. or i.p. administration in the swine contact hypersensitivity model, ABT-281 was 19- and 61-fold less potent, respectively, than FK506. Pharmacokinetic studies showed that ABT-281 had a shorter half life and higher rate of clearance than FK506 in all three species. The potent topical activity and reduced systemic exposure of ABT-281 may thus provide both efficacy and a greater margin of safety for topical therapy of skin diseases.

Administration, Topical↗
PubMed1991

Attenuation of the pulmonary vascular response to endotoxin by a thromboxane synthesis inhibitor (UK-38485) in unanesthetized sheep.

Previous studies have documented the phasic pulmonary vascular response to infused Escherichia coli endotoxin in unanesthetized sheep. Cyclooxygenase inhibition attenuates the initial vasoconstrictive phase (phase I) but not the late phase of increased microvascular permeability (phase II). We undertook to selectively inhibit thromboxane A2 synthesis and assess the pulmonary microvascular response to endotoxin. Twelve paired studies were carried out in six sheep prepared with chronic lung lymph fistulas and pressure monitoring catheters. Each sheep received E. coli endotoxin (0.5 microgram/kg) at time 0, both alone (control group) and 1 hr after pretreatment with a thromboxane synthetase inhibitor (UK-38485, 2 mg/kg). The animals were monitored for 1-2 hr prior to and 5 hr following endotoxin infusion to ensure a steady-state baseline and a complete late response. The pairs of studies were done in random order. In the presence of UK-38485, endotoxin caused significantly less pulmonary hypertension and shorter duration of leukopenia and lower lung lymph flow and lymph protein clearance rates than did endotoxin alone. The differences in lymph protein clearance were more pronounced in phase II. These data suggest that both the vasoconstrictive and permeability phases of the pulmonary vascular response to endotoxin may be modified on endogenous thromboxane A2.

Animals↗
PubMed1985

Tetralogy of Fallot: selective surgical management can minimize operative mortality.

Although tetralogy of Fallot can be completely corrected at any age, it appears that preliminary shunting may be of benefit in infancy. To better define the optimum age for shunting, the following patient data were reviewed. One hundred five patients with tetralogy of Fallot were treated between December, 1975, and July, 1984. Eight of 100 patients undergoing intracardiac repair died. Operative mortality was 14.3% (4 of 28 patients) when intracardiac repair was done before the patient was a year old, but only 5.6% (4 of 72 patients) after that age. Seven (13%) of 54 patients requiring transannular patch reconstruction of the right ventricular outflow tract died, whereas only 1 (2.2%) of 46 having repair without this type of reconstruction died (p less than 0.05). Twenty-one patients were initially palliated with systemic-pulmonary artery shunts, with 1 noncardiac death related to associated congenital neurological anomalies (4.8%). There was no statistically significant difference in mortality for primary versus secondary intracardiac repair. Left ventricular end-diastolic volume determination in 26 patients less than 2 years old demonstrated that 14 patients had small left ventricles and that 3 of them less than 1 year of age died at corrective operation. The remaining 12 had a left ventricle of normal size, and 1 of them died at operation. Palliative shunts can be performed safely in the very young child with no increased mortality at subsequent intracardiac repair. Diffuse hypoplasia of the right ventricular outflow tract and pulmonary arteries requiring transannular patch reconstruction, and age less than 1 year both alter operative mortality, their combined impact being additive.

Adolescent↗
PubMed1983

Not just fibre--the nutritional consequences of refined carbohydrate foods.

The dietary intake of 28 volunteers was assessed over two 6-week periods while they ate, alternately, a diet containing refined carbohydrate foods in commonly consumed amounts and a diet virtually devoid of such foods. The following nutritional effects of refined foods were observed: increased energy intake (except in low consumers of sugar), decreased intake of dietary fibre, and decreased intake of nearly all the vitamins and minerals recorded in tables of food composition. These effects may have harmful consequences.

Adult↗
PubMed1981

Unrefined carbohydrate and dietary fibre in treatment of diabetes mellitus.

Sixteen diabetics were studied over six-week periods on two diets--a conventional carbohydrate-restricted diet and a diet which excluded all refined (fibre-depleted) carbohydrate but which allowed unrefined (fibre-intact) carbohydrate freely. On the latter, there was a substantial increase in dietary fibre intake. Despite this, there was no change in 24-h urinary excretion of glucose nor in blood glycosylated haemoglobin concentration, and there was only a modest improvement in post-prandial plasma glucose concentration. We suggest that simply switching from refined to unrefined cereal foods without increasing total carbohydrate intake is unlikely to produce much improvement in diabetic control.

Adult↗
PubMed1981

Diet and the diabetic: the fallacy of a controlled carbohydrate intake.

The dietary intake of 16 well-established diabetics was recorded over six-week periods on two different diets--a conventional, carbohydrate-controlled diet and an unrestricted, carbohydrate diet which allowed free choice as to quantity of food eaten and time of meals. In all patients the carbohydrate intake varied considerably from day to day and the variation was as great on the supposedly controlled carbohydrate diet as on the unrestricted diet. In agreement with other studies, carbohydrate intake was often considerably higher on the usual diabetic diet than had been recommended or than the patient believed they were taking. It is suggested that present methods for controlling the carbohydrate intake of diabetics are ineffective and, in particular, do not ensure a regular intake from day to day.

Adult↗
PubMedDate not supplied

Wastewater dewatering polymer affect on biosolids odor emissions and microbial activity.

Odor emissions and microbial activity associated with biosolids dewatered using seven different polyacrylamide cationic polymers were investigated. Nitrogen, sulfur, ketone, and odor unit emissions, and biosolids microbial community metabolic profiles were measured for biosolids containing each polymer. Ammonia represented more than 98% of total nitrogen flux for all polymers, with small concentrations of trimethyl amine. Dimethyl disulfide and carbon disulfide fluxes summed represented 87 to 97% of the sulfur flux for all polymers, with lesser quantities of dimethyl sulfide. Maximum dimethyl disulfide, ammonia, and trimethyl amine concentrations were estimated to be 3.4, 3.2, and 13.5 times greater than published detection limits, respectively. Maximum dimethyl sulfide, carbon disulfide, acetone, and methyl ethyl ketone concentrations were estimated to be 0.028, 0.007, 0.002, and 0.0006 times less than published detection limits, respectively. All treatments were found to volatilize equal odor unit emissions (with the exception of one polymer), and polymers were not found to dramatically affect odor emission from biosolids application. Metabolic fingerprints revealed differences in the ability of microbial communities from certain polymer treatments to degrade amino acids as a sole carbon substrate. In addition, odor unit emissions were significantly correlated with potential for amino acid decomposition.

Amino Acids↗