Reduced spontaneous but relatively normal deliberate vicarious representations in psychopathy.

Psychopathy is a personality disorder associated with a profound lack of empathy. Neuroscientists have associated empathy and its interindividual variation with how strongly participants activate brain regions involved in their own actions, emotions and sensations while viewing those of others. Here we compared brain activity of 18 psychopathic offenders with 26 control subjects while viewing video clips of emotional hand interactions and while experiencing similar interactions. Brain regions involved in experiencing these interactions were not spontaneously activated as strongly in the patient group while viewing the video clips. However, this group difference was markedly reduced when we specifically instructed participants to feel with the actors in the videos. Our results suggest that psychopathy is not a simple incapacity for vicarious activations but rather reduced spontaneous vicarious activations co-existing with relatively normal deliberate counterparts.

Intraoperative high resolution duplex imaging during carotid endarterectomy: which abnormalities require surgical correction?

OBJECTIVES: This study evaluates high resolution, duplex ultrasound imaging for quality control of carotid endarterectomy in order to determine which technical factors were linked to residual stenosis and to define duplex criteria for re-exploration. DESIGN, MATERIAL AND METHODS: A consecutive series of 100 patients undergoing carotid endarterectomy were evaluated. Duplex imaging was performed prior to wound closure and repeated at 6-8 weeks postoperatively. Stenoses were classified as non-significant, moderate or severe based on duplex criteria. Intimal flaps, shelves, kinks, clamp damage and fronds were identified by ultrasound imaging. RESULTS: Five moderate stenoses were noted in the proximal endarterectomy site (PES), and at follow-up three had resolved. Adherent fronds were detected in 83% of vessels and resolved in all but three cases. At the distal endarterectomy site there were 10 severe and 12 moderate stenoses. Intimal flaps were associated with an increased incidence of residual stenosis (p = 0.010). CONCLUSIONS: We conclude that severe stenoses with an intimal flap should be corrected immediately. Further data is required to establish the significance of kinks. Residual intimal flaps in the PES appear to remodel. The role of completion duplex may lie in the modification of surgical technique to eradicate anatomical and haemodynamic imperfections.

Tamm-Horsfall protein in reflux nephropathy.

The distribution of Tamm-Horsfall protein, the main protein in normal urine, was studied immunohistologically in the kidneys of 70 pigs with unilateral vesico-ureteric reflux but without outflow obstruction. Strains of Escherichia coli were inoculated in the bladder. Inflammatory changes of reflux nephropathy (chronic pyelonephritis) were found in 52 pigs. There were extra-tubular deposits of Tamm-Horsfall protein in the kidneys of only 26 pigs. These deposits were small, increased in prevalence as the size of inflamed areas increased, and were not associated with deposits of the protein in glomeruli. These findings suggest that escape of Tamm-Horsfall protein from tubules and backwash into glomeruli are not major features of low pressure reflux nephropathy, unlike the findings in outflow obstruction of the lower urinary tract. There was no evidence that a reaction to Tamm-Horsfall protein was important in the pathogenesis of reflux nephropathy.

Bacterial factors in the formation of renal scars. An experimental study on the role of Escherichia coli P-fimbriation and hydrophobicity.

A model capable of comparing the effects of bacterial virulence factors on renal scarring in vivo has been developed using the female piglet. By creating, at open surgery, unilateral vesicoureteric reflux (VUR) and quantifying scarring both by uptake of an isotope bound to functioning renal parenchyma and by planimetry of the surface area scarred, the effects of 2 organisms, a P-fimbriate Escherichia coli and an E. coli K1 have been compared. The P-fimbriate E. coli was shown to express P-fimbriae in freshly voided urine, was more hydrophobic and produced smaller scars. This indicates that neither the hydrophobicity nor P-fimbriation of the organism causing urinary tract infection (UTI) is of prime importance for the development of renal scars and is evidence against the "big bang" theory for the development of renal scars. Studies on the association of UTI with VUR showed that infection with both E. coli under study led to VUR on the side contralateral to the side undergoing surgery. It seems likely that a non-specific effect of UTI, such as bladder oedema, is responsible for this acquired VUR. An effect of the 2 bacteria under study on the lower urinary tract was observed in that infection with the P-fimbriate E. coli allowed the retention of an intravesical wax plug, whereas infection with E. coli K1 did not. Epidemiological data have shown that the majority of upper urinary tract infections in children are associated with UTI by P-fimbriate organisms. Such an association may be explained in part by an effect of P-fimbriate bacteria on lower urinary tract function rather than an effect on the upper urinary tract.

Reconsideration of the roles of urinary infection and vesicoureteric reflux in the pathogenesis of renal scarring.

In an experimental study of female piglets with surgically created unilateral vesicoureteric reflux, Escherichia coli were inoculated into the bladder and, at later sacrifice, bacterial culture was undertaken of renal parenchyma from the refluxing and non-refluxing kidneys. Positive cultures of the same E. coli were obtained from 33% of refluxing kidneys with pyelonephritic renal scars, 23% of refluxing kidneys without scars and 21% of non-refluxing kidneys. Although other aspects of the experiments confirmed that a combination of urinary infection, vesicoureteric reflux and intra-renal reflux is a necessary precondition for renal scarring, these findings indicate that reflux plays a role in the pathogenesis of renal scarring over and above a means whereby pathogens gain access from the lower urinary tract to the renal substance. Possible mechanisms are discussed.

Imidazoquinoline derivatives: potent inhibitors of platelet cAMP phosphodiesterase which elevate cAMP levels and activate protein kinase in platelets.

Compounds containing the imidazoquinoline nucleus are a new class of potent, broad-spectrum inhibitors of platelet aggregation. This report describes studies with a simply-substituted imidazoquinoline (BMY 20844) and several new ether-linked side chain derivatives (BMY 21638 and BMY 43351). These compounds are potent inhibitors of platelet cAMP phosphodiesterase (IC50 values: BMY 20844, 1.3 X 10(-8); BMY 21638, 2 X 10(-10); and BMY 43351, 1 X 10(-10) M, measured using 0.15 microM cAMP) but have little effect on platelet homogenate cGMP phosphodiesterase (IC50 greater than 10(-5) M). Inhibition of different cAMP phosphodiesterase isozymes was tested to determine if the compounds inhibited similar isozymes in other tissues. Rabbit heart cAMP phosphodiesterase isozymes were resolved by ion-exchange chromatography and three peaks of activity were obtained. BMY 20844 inhibited only fraction III (a "cGMP-inhibitable, low Km" cAMP-specific phosphodiesterase) with an IC50 value of 5 X 10(-8) M. These compounds also inhibited canine cardiac sarcoplasmic reticulum membrane-bound "cGMP-inhibitable, low Km" cAMP-specific phosphodiesterase with virtually the same potency as inhibition of cAMP phosphodiesterase in platelet homogenate. In washed platelets these compounds elevated cAMP levels and activated the platelet cAMP dependent protein kinase. Activation of cAMP-dependent protein kinase was determined by cAMP-dependent protein kinase ratio measurements and phosphorylation of intracellular proteins. These studies suggest that this potent new class of agents inhibits platelet phosphodiesterase activity in intact platelets causing an elevation in cAMP levels sufficient to activate the cAMP-dependent protein kinase and stimulate protein phosphorylation. This mechanism is, at least in part, responsible for the ability of these compounds to prevent platelet aggregation and thrombosis in experimental animal models.

Octimibate inhibition of platelet aggregation: stimulation of adenylate cyclase through prostacyclin receptor activation.

Octimibate inhibited ADP- and collagen-induced platelet aggregation in human, rabbit and rat platelet-rich plasma. Washed human platelets treated with octimibate had elevated cyclic AMP (cAMP) levels and cAMP-dependent protein kinase activity. When whole platelets were incubated with radiolabeled phosphate, octimibate produced an increase in the phosphorylation of platelet proteins with relative molecular weights of 22, 26, 50 and 80 kilodaltons. This pattern of protein phosphorylation is identical to that observed when the platelets were treated with forskolin, phosphodiesterase inhibitors or other compounds that elevate platelet cAMP levels. Octimibate also inhibited the rise in intracellular Ca++ caused by thrombin, as measured using Fura-2-loaded platelets, which is consistent with octimibate's ability to elevate platelet cAMP levels. When isolated platelet plasma membranes were treated with octimibate, adenylate cyclase activity was stimulated, reaching maximal activation at 1 microM octimibate. (The maximal activation of adenylate cyclase observed with octimibate is 70-75% of that observed with 10 microM PGE1.) This stimulation of platelet adenylate cyclase activity was enhanced by GTP. Octimibate competed for radiolabeled prostaglandin E1 and lloprost binding to isolated platelet membranes at submicromolar concentrations, but did not compete with radiolabeled prostaglandin D2 binding. These studies suggest that octimibate inhibits platelet aggregation by activating platelet adenylate cyclase through stimulation of platelet prostacyclin receptors.

Current management of childhood neuropathic bladder: review of 156 cases.

Management of neuropathic bladder aims to maintain renal function and to secure appliance-free continence; because of recent advances, both objectives are theoretically attainable. Our present scheme of management, based upon preliminary video-urodynamic assessment, is outlined. In the years 1984-1988 we treated 156 children suffering from neuropathic bladder. In 5 per cent of cases the upper renal tracts have deteriorated on treatment; in patients presenting with upper tract dilatation, improvement has been obtained in 68 per cent. A quarter of the patients were considered too generally disabled to achieve appliance-free continence; these have been managed by penile appliance, indwelling urethral catheter or, occasionally, urinary diversion. For three-quarters of the patients, most ambulant, appliance-free continence was the goal; 68 per cent have been managed nonsurgically and 32 per cent surgically. Reliable day-time continence has been achieved in 78 per cent of the former and 86 per cent of the latter, 80 per cent overall.

The bilateral dog-ear transposition flap.

An original technique is presented for the closure of circular defects that cannot be closed primarily without undue tension. The technique involves the creation of dog-ear tissue, which is then fully utilized in the closure. The technique involves no sacrifice of normal tissue and results in a relatively short, cosmetically acceptable scar.

Detection of renal scarring by DMSA scanning--an experimental study.

Using the established piglet model, renal scars were produced by a combination of vesicoureteric reflux and urinary infection. The presence and extent of scarring, as determined by postmortem examination, was compared with that detected by technetium 99m dimercaptosuccinic acid (DMSA) scans performed before sacrifice. Sixty female piglets (62 refluxing units) were studied. Overall the sensitivity (true-positive/(true-positive + false-negative)) of DMSA scanning in detecting macroscopic scarring was 85% and the specificity (true-negative/(true-negative + false-positive)) was 97%. There were five false-negatives, four of which were in kidneys with minor scarring and one in which there was major scarring. There were three false-positives. We conclude that DMSA scanning has a high specificity and sensitivity in detecting renal scars in female piglets, and suggest it is the preferred method for detecting renal scars in clinical practice.

Natural history of pelviureteric obstruction detected by prenatal sonography.

Fifty-six infants with prenatally diagnosed hydronephrosis are reported. In all instances the diagnosis was confirmed postnatally and at renography 45 were obstructed; 38 obstructed kidneys (84%) and all of the non-obstructed kidneys had a differential function exceeding 40% of total function. Latterly we have come to recommend early pyeloplasty only if differential function of a renographically obstructed kidney is less than 40%; 6 early pyeloplasties were performed for this reason; 28 infants (30 renal units) were managed non-operatively and 18 of these (19 renal units) were reassessed renographically. In 11 the obstruction persists. Sonography demonstrated improving hydronephrosis in 8 kidneys with resolution in 5 and no change in 6. Of the other 10 infants (11 renal units), the hydronephrosis has improved in 4, resolved in 1 and remains unchanged in 6. Our experience suggests that neonatal and early pyeloplasty can be restricted to a modest number of infants in whom there is impaired renal function. In cases with normal function the natural history appears essentially benign and does not justify routine pyeloplasty.

Subcapsular orchiectomy under local anaesthesia. Technique, results and implications.

One hundred patients with carcinoma of the prostate have been treated by bilateral subcapsular orchiectomy under local anaesthesia over a 5-year period. The indications, technique and results of performing the operation in this way are described. The procedure is simple, effective and well tolerated by the patients.

Effects of anagrelide on platelet cAMP levels, cAMP-dependent protein kinase and thrombin-induced Ca++ fluxes.

Anagrelide (BL-4162A, 6,7-dichloro-1,5-dihydroimidazo[2, 1-6] quinazolin-2[3H]one monohydrochloride hydrate) is a potent and broad spectrum inhibitor of platelet aggregation. Prior studies showed that anagrelide inhibited platelet cyclic AMP (cAMP) phosphodiesterase activity but did not appreciably elevate platelet cAMP levels. We examined the effects of anagrelide on washed human platelets and found that anagrelide caused significant elevation of cAMP levels. Anagrelide treatment also resulted in activation of the platelet cAMP-dependent protein kinase at anagrelide concentrations of 0.1 to 1 microgram/ml, which inhibited platelet aggregation but caused only small increases in platelet cAMP content. When whole platelets were incubated with radiolabeled phosphate, anagrelide increased phosphorylation of platelet proteins with relative molecular weights of 22, 26, 50 and 80 kilodaltons. The pattern of protein phosphorylation stimulated by anagrelide treatment was similar to that observed when the platelets were treated with forskolin. Anagrelide also inhibited the rise in intracellular Ca++ caused by thrombin, as measured using Fura-2-loaded platelets. The inhibition of increased intracellular Ca++ resulted from block of thrombin-induced mobilization of intracellular Ca++, as well as prevention of Ca++ influx through the plasma membrane. Anagrelide itself had no influence on inositol 1,4,5-trisphosphate-induced Caz5++ release from isolated platelet membrane vesicles. These studies suggest that anagrelide inhibits platelet phosphodiesterase activity in intact platelets resulting in an elevation in cAMP levels sufficient to activate the cAMP-dependent protein kinase and inhibit agonist-activated Ca++ fluxes.

Inhibitors of inositol trisphosphate-induced Ca2+ release from isolated platelet membrane vesicles.

Platelet membrane vesicles accumulated Ca2+ in an ATP-dependent fashion, and 25-50% of the accumulated Ca2+ was released by the addition of 10 microM inositol 1,4,5-trisphosphate (IP3). The concentration of IP3 required for half-maximal Ca2+ release was approximately 0.5 microM. The inhibition of IP3-induced Ca2+ release from these membrane vesicles by various agents was examined. Of the plasma membrane Ca2+ channel blockers, cinnarizine and flunarizine were found to be potent inhibitors of IP3-induced Ca2+ release while having no effect on ATP-dependent Ca2+ uptake. The IC50 value for both cinnarizine and flunarizine as inhibitors of IP3-induced Ca2+ release was below 10(-6) M. Nifedipine, verapamil, bepridil, and diltiazem did not significantly inhibit IP3-induced Ca2+ release at the highest concentration tested (50 microM). The "intracellular Ca2+ antagonists" ryanodine, TMB-8 (8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate), dantroline, trifluoperazine and chlorpromazine were not inhibitors of IP3-induced Ca2+ release at 50 microM. The local anesthetics benzocaine and lidocaine weakly inhibited the IP3-induced Ca2+ release with IC50 values of approximately 5 and 50 microM, respectively, whereas other local anesthetics tested were less potent inhibitors. The potent inhibitors described may prove useful as probes of the IP3-induced Ca2+ release channels.

Calcium antagonizes 1,25-dihydroxyvitamin D3 inhibition of breast cancer cell proliferation.

The hormone 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] inhibited proliferation of two breast cancer cell lines (HT-39 and MCF-7) in a dose-dependent manner. We showed that 10 nM 1,25-(OH)2D3 inhibited HT-39 cell growth by 26.3 +/- 3.2% and MCF-7 proliferation by 19.5 +/- 8.6% (mean +/- SE). When both cell lines were cultured in the presence of medium containing varying concentrations of calcium, analysis of cell growth revealed that lowering the medium Ca2+ concentration from 1.3 to 0.1 mM inhibited cell proliferation of HT-39 cells by 20.0 +/- 2.3% and that of MCF-7 cells by 13.4 +/- 3.4% (mean +/- SE). Raising medium Ca2+ from 1.3 to 2.6 mM stimulated cell proliferation of HT-39 cultures by 51.8 +/- 2.3% and that of MCF-7 cells by 13.3 +/- 3.3% (mean +/- SE). When HT-39 cells were grown in medium containing different calcium levels and dosed with 10 nM 1,25-(OH)2D3, we found that the inhibitory action of 1,25-(OH)2D3 was modified. HT-39 cells in medium containing 0.1 mM calcium were more potently inhibited by 10 nM 1,25-(OH)2D3 (increased by 74% relative to that in cells in 1.3 mM calcium). Moreover, the inhibitory action of 1,25-(OH)2D3 (10 nM) on HT-39 cells grown in 2.6 mM calcium media was decreased by 68% relative to that in cells in 1.3 mM extracellular calcium. The phorbol ester 4 beta-phorbol 12,13-dibutyrate (PDB) stimulated HT-39 proliferation by 30.1 +/- 4.1%. Cells treated with PDB showed increased cell mitotic index, but unlike extracellular calcium, PDB had no effect on the dose response of 1,25-(OH)2D3 to inhibit HT-39 cell growth. We show that 1,25-(OH)2D3 action on malignant cell proliferation is dependent on the extracellular calcium concentration. The data suggest that the effect of calcium to antagonize 1,25-(OH)2D3 on HT-39 cells is not shared by all agents (e.g. PDB) that increase HT-39 cell proliferation.

Identification of 1,25-dihydroxyvitamin D3 receptors and activities in muscle.

Cytosols from cultured myoblast cells (G-8 and H9c2) prepared in high salt (0.3 M KCl) possesses receptor like proteins for 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) that sediment in the 3.2 S region of sucrose gradients. These receptors were characterized as having high affinity (Kd less than 0.1 nM) for 1,25-(OH)2D3 and are in low capacity (less than 80 fmol/mg of cytosol protein). Analog competition for receptor binding revealed that 1,25-(OH)2D3 was more potent than 24,25-(OH)2D3, or 25-(OH)2D3 for displacement of 1,25-(OH)2[3H]D3 from these 3.2 S region sedimenting receptors. Furthermore, the receptor proteins had affinity for DNA and eluted from Sephacryl S-200 as a macromolecule with Stokes radius (Rs) of 32 A. High salt cytosol from collagenase-dispersed skeletal muscle cells was also found to possess a 3.2 S 1,25-(OH)2D3 receptor-like protein. The 1,25-(OH)2D3 receptor concentration in both G-8 and H9c2 myoblast lines was found to down-regulate by 50-70% when cells were stimulated to differentiate to myotubes by lowering fetal calf serum to 5% of the medium. Moreover, we demonstrated that 1,25-(OH)2D3 can inhibit DNA synthesis and cell proliferation of the G-8 myoblast cells in a dose-dependent manner. 1,25-(OH)2D3 was more potent at inhibiting cell proliferation in cells grown in 5% serum than in 20% serum. The data suggest that 1,25-(OH)2D3 can act directly on muscle myoblast via a 1,25-(OH)2D3 receptor that is similar to those found in intestine and bone. The data support the possibility that muscle is a target tissue for 1,25-(OH)2D3 and the hormone may act to initiate terminal differentiation of myoblast cells.