Biomedical subjects

J N Weiss

Publications and source records attributed to J N Weiss.

At least 109 records · Page 6Linked to original sources

PubMed1989

Clinical photon correlation spectroscopy evaluation of human diabetic lenses.

Clinical research on cataract prevention requires an in vivo assessment of the lens of the eye that is non-invasive, quantitative and detects lens changes that precede lens opacification or cataract formation. The method of photon correlation spectroscopy or quasi-elastic light scattering spectroscopy provides such a non-invasive probe. The measurement, based on fluctuations in scattered light intensity caused by translational Brownian motion of the lens proteins, allows a determination of a protein diffusion coefficient and hence information on quaternary conformational changes of these protein scatterers. These protein changes have been observed in association with the presence of lens opacification. The occurrence of these changes prior to opacification, however, has still to be established. The analyses performed in this study were aimed at testing the hypothesis of an association between subclinical molecular changes in the lens as measured by quasi-elastic light scattering and the presence of selected risk factors for cataract. Measurements were made from 393 diabetics attending the Joslin Diabetes Center Eye Unit and 38 non-diabetic volunteers. Measurements at two different instrument sample times, 1.5 microseconds and 150 microseconds, allowed characterization of two different protein size distributions contributing to the quasi-elastically light scattered signal. Measurements performed at the 1.5 microseconds sample time demonstrated significantly decreased lens protein diffusivity in association with older age, higher grade of nuclear sclerosis and presence of diabetes. Statistically significant associations were also observed between lens protein diffusivity and diabetes related factors such as glycosylated hemoglobin level (diabetes control), duration of diabetes, age at onset of diabetes and type of diabetic therapy. The pattern of association exhibited between decreased protein diffusion coefficient and risk factor status is consistent with the patterns of increased risk previously demonstrated in cataract formation. Measurements performed at the 150 microseconds sample time demonstrated significantly decreased lens protein diffusivity in association with increasing age, female sex and glycosylated hemoglobin level. These associations differed significantly from those observed at the 1.5 microsecond sample time, thereby suggesting that these two sample times assess different species of lens proteins. The results of this analysis demonstrate the clinical utility of quasi-elastic light scattering as a rapid, non-invasive method to quantitate lens changes and assess methods of cataract prevention and treatment.

Adolescent↗

PubMed1989

Fractionated endocardial electrograms are associated with slow conduction in humans: evidence from pace-mapping.

Fractionated ventricular electrograms recorded during catheter mapping may arise from areas of asynchronous depolarization associated with slow conduction, the substrate for reentrant ventricular tachycardia, but can also be a nonspecific abnormality or even artifact. To determine whether fractionated sinus rhythm electrograms are associated with slow conduction in humans, the results of endocardial catheter mapping and pacing at 133 endocardial sites in 13 patients were analyzed. Eleven patients had sustained monomorphic ventricular tachycardia and two patients had old myocardial infarction without ventricular tachycardia. Functional evidence of slow conduction at the recording site was assessed by pacing at that site and measuring the interval between the stimulus artifact (S) and the onset of the QRS complex in the 12 lead electrocardiogram (ECG). During pacing at 89 of 90 sites without fractionated sinus rhythm electrograms, the S-QRS interval was less than 40 ms, a value consistent with rapid propagation of the stimulated wave front away from the pacing site. During pacing at 21 (49%) of 43 sites with fractionated sinus rhythm electrograms, the S-QRS interval was greater than 40 ms (range 40 to 140), consistent with slow conduction at the pacing site (p less than 0.001 versus nonfractionated sites). In 9 of the 11 patients with ventricular tachycardia analysis of the paced QRS configuration, electrograms during induced ventricular tachycardia or programmed stimulation during tachycardia suggested that a site with a long S-QRS interval during pacing was located at or near a ventricular tachycardia circuit. Therefore, fractionated sinus rhythm electrograms are often associated with slow conduction, which may be the substrate for reentrant ventricular tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1989

Cardiac ATP-sensitive K+ channels. Evidence for preferential regulation by glycolysis.

The ability of glycolysis, oxidative phosphorylation, the creatine kinase system, and exogenous ATP to suppress ATP-sensitive K+ channels and prevent cell shortening were compared in patch-clamped single guinea pig ventricular myocytes. In cell-attached patches on myocytes permeabilized at one end with saponin, ATP-sensitive K+ channels were activated by removing ATP from the bath, and could be closed equally well by exogenous ATP or substrates for endogenous ATP production by glycolysis (with the mitochondrial inhibitor FCCP present), mitochondrial oxidative phosphorylation, or the creatine kinase system. In the presence of an exogenous ATP-consuming system, however, glycolytic substrates (with FCCP present) were superior to substrates for either oxidative phosphorylation or the creatine kinase system at suppressing ATP-sensitive K+ channels. All three groups of substrates were equally effective at preventing cell shortening. In 6 of 38 excised inside-out membrane patches, ATP-sensitive K+ channels activated by removing ATP from the bath were suppressed by a complete set of substrates for the ATP-producing steps of glycolysis but not by individual glycolytic substrates, which is consistent with the presence of key glycolytic enzymes located near the channels in these patches. Under whole-cell voltage-clamp conditions, inclusion of 15 mM ATP in the patch electrode solution dialyzing the interior of the cell did not prevent activation of the ATP-sensitive K+ current under control conditions or during exposure to complete metabolic inhibition. In isolated arterially perfused rabbit interventricular septa, selective inhibition of glycolysis caused an immediate increase in 42K+ efflux rate, which was prevented by 100 microM glyburide, a known blocker of ATP-sensitive K+ channels. These observations suggest that key glycolytic enzymes are associated with cardiac. ATP-sensitive K+ channels and under conditions in which intracellular competition for ATP is high (e.g., in beating heart) that act as a preferential source of ATP for these channels.

Adenosine Diphosphate↗

PubMed1989

Neuraminidase selectively enhances transient Ca2+ current in cardiac myocytes.

Sialic acid, an anionic sugar moiety found peripherally on membrane glycoconjugates, is specifically hydrolyzed from the cell surface by neuraminidase. Because neuraminidase has previously been demonstrated to augment myocardial cell calcium content, the effects of neuraminidase on Ca channel function were studied on voltage-clamped guinea pig ventricular myocytes. In 25-50% of cells, neuraminidase treatment (0.12 U/ml for 20 min) enhanced current through the transient (T) Ca channel by 304 +/- 35% without significantly altering the magnitude of the long-lasting (L) Ca channel current. Exposure to neuraminidase did not affect the voltage dependence of activation or inactivation, nor did it affect the selective inhibition of the T-channel current by amiloride or the L-channel current by nifedipine. After neuraminidase treatment, the T-channel current inactivated more rapidly (time constant decreasing from 8.9 +/- 0.9 to 7.7 +/- 0.6 ms), whereas there was no change in the rate of inactivation of the L-channel current. Neuraminidase treatment removed approximately 20% of the total cellular sialic acid. These results indicate that neuraminidase treatment selectively modulates the function of the T Ca channel in ventricular myocytes, possibly through removal of sarcolemmal sialic acid, suggesting that glycosylation of membrane macromolecules may influence membrane function.

Animals↗

PubMed1989

Cellular K+ loss and anion efflux during myocardial ischemia and metabolic inhibition.

It has been suggested that increased K+ efflux during myocardial hypoxia and ischemia may result from efflux of intracellularly generated anions such as lactate and inorganic phosphate (Pi) as a mechanism of balancing transsarcolemmal charge movement. To investigate this hypothesis cellular K+ loss using 42K+ and K+-sensitive electrodes, intracellular potential, venous lactate and Pi, and tissue lactate and high-energy phosphates were measured in isolated arterially perfused rabbit interventricular septa during exposure to metabolic inhibitors, hypoxia, and ischemia. Selective inhibition of glycolysis caused a marked increase in K+ efflux despite a fall in lactate production and maintenance of normal cellular high-energy phosphate content. During ischemia and hypoxia net loss of lactate and Pi exceeded K+ loss by a factor of 2-6. However, removal of glucose prior to ischemia or during hypoxia increased K+ loss but reduced lactate loss without affecting Pi loss. During hypoxia, 30 mM exogenous lactate did not alter K+ loss in a manner consistent with changes in passive electrodiffusion of lactate ion. These findings inhibition which is not related to anion efflux assumes greater importance under conditions in which glycolysis is inhibited, e.g., ischemia. Under conditions in which glycolysis is not inhibited, e.g., hypoxia, K+ efflux does not parallel passive electrodiffusion of lactate ions. However, this finding does not exclude the possibility that K+ loss could be coupled to carrier-mediated lactate ion efflux.

Adenosine Triphosphate↗

PubMed1989

Programmed electrical stimulation at potential ventricular reentry circuit sites. Comparison of observations in humans with predictions from computer simulations.

The purpose of this study was to define specific types of resetting responses to programmed electrical stimulation during human ventricular tachycardia and to use computer simulations of reentry circuits to assess the possible mechanisms and pacing site location relative to the reentry circuit for each type of response. The effects of scanning single stimuli at 35 left ventricular endocardial sites during sustained monomorphic ventricular tachycardia in 12 patients were studied. In considering alterations in QRS configuration and the delay between the stimulus and the advanced QRS, we identified three types of resetting responses to scanning stimuli consistent with stimulation at sites in or near the reentry circuit at 12 abnormal endocardial sites in eight patients. Type 1: all capturing stimuli were followed after a delay by early QRS complexes that had the same configuration as the tachycardia complexes. Type 2: late stimuli reset tachycardia as in type 1 but early stimuli reset the tachycardia after altering the QRS configuration. Type 3: late stimuli reset tachycardia as in type 1, but early stimuli advanced tachycardia with a short stimulus to QRS delay without altering the QRS configuration. In the simulations, premature depolarization of sites in the circuit produced orthodromic and antidromic wavefronts. The orthodromic wavefront propagated through the circuit and exited the circuit at the same site as did the previous tachycardia wavefronts and advanced the tachycardia without altering the configuration of the advanced QRS. The antidromic wavefront of relatively late stimuli was confined within or near the circuit by collision with the orthodromic wavefront of the preceding tachycardia beat and failed to alter ventricular activation distant from the circuit. Therefore, the QRS configuration after the stimulus was unchanged. A type 1 response occurred when all capturing stimuli produced this effect. However, with increasing stimulus prematurity, the antidromic wavefront propagated farther before colliding with an orthodromic wavefront, and under some conditions, it exited the circuit from a site other than the original circuit "exit," and altered the ventricular activation sequence distant from the circuit and, therefore, the QRS configuration, producing a type 2 pattern. The type 3 pattern occurred when the antidromic wavefront of early premature beats captured the original circuit exit. The effect of a stimulus was dependent on the stimulus prematurity, the relative conduction times from the stimulation site to the potential sites of "exit" from the circuit, and the timing of the excitable gap at the stimulation site.(ABSTRACT TRUNCATED AT 400 WORDS)

Cardiac Pacing, Artificial↗

PubMed1989

Effects of exogenous free radicals on electromechanical function and metabolism in isolated rabbit and guinea pig ventricle. Implications for ischemia and reperfusion injury.

Oxygen-derived free radicals have been implicated in the pathogenesis of cardiac dysfunction during ischemia, postischemic myocardial "stunning," and reperfusion injury. We investigated the effects of oxygen-derived free radicals on cardiac function in intact isolated rabbit hearts and single guinea pig ventricular myocytes. In the intact rabbit ventricle, exposure to free radical-generating systems caused increased cellular K+ efflux, shortening of the action potential duration, changes in tension, and depletion of high energy phosphates similar to ischemia and metabolic inhibition. In patch-clamped single ventricular myocytes, free radical-generating systems activated ATP-sensitive K+ channels, decreased the calcium current, and caused cell shortening by irreversibly inhibiting glycolytic and oxidative metabolism. The results suggest that free radicals generated during ischemia and reperfusion may contribute to electrophysiologic abnormalities and contractile dysfunction by inhibiting glycolysis and oxidative phosphorylation. Inhibition of metabolism by free radicals may be an important factor limiting functional recovery from an ischemic insult after reestablishment of effective blood flow.

Adenosine Triphosphate↗

PubMed1989

The effect of acute changes in blood glucose on lenses in diabetic and non-diabetic subjects using quasi-elastic light scattering spectroscopy.

Quasi-elastic light scattering spectroscopy was used to non-invasively monitor affects of transient blood glucose changes on lenses of non-diabetic subjects undergoing glucose tolerance testing and diabetic subjects undergoing glucose clamping protocols. Non-diabetic subjects exhibited a characteristic biphasic change in lens protein diffusion coefficient in response to glucose loading. There was an initial rapid decrease in diffusion coefficient followed by an increase to a maximum attained approximately 30 minutes after peak blood glucose levels had been reached. The diffusion coefficients then returned to baseline values approximately 60 minutes later. These changes in diffusion coefficient in the non-diabetic lens may be related to changes in lens hydration in response to glucose loading. Diabetic subjects, in contrast, did not exhibit a marked change in diffusion coefficient in response to acute blood glucose level changes. This may be attributed to an osmotic buffering in the diabetic lens which could offset the transient changes in aqueous glucose levels.

Adult↗

PubMed1988

Complicated atherosclerotic lesions: a potential cause of ischemic ventricular arrhythmias in cardiac arrest survivors who do not have inducible ventricular tachycardia?

Sudden cardiac death that is not due to acute myocardial infarction may be due to primary ventricular tachycardia or to an arrhythmia secondary to a transient episode of ischemia. The purpose of this study was to determine if the incidence of complicated coronary lesions, which may be a cause of unstable ischemic syndromes, is increased in survivors of an aborted sudden death, especially those without ventricular tachycardia inducible by programmed ventricular stimulation. Nineteen consecutive survivors of an aborted sudden death not due to an acute infarction who underwent coronary angiography and programmed ventricular stimulation within 3 weeks of the event were matched for age, sex, previous infarction, and severity of coronary artery disease with 38 control patients with stable coronary artery disease. There was no difference in the incidence of complicated coronary lesions between the total group of sudden death victims and controls (47% vs 42%). However, 6 of the 11 (64%) sudden death patients who did not have inducible ventricular tachycardia had a complicated lesion as compared to only two of the eight (25%) patients with inducible ventricular tachycardia (p = 0.10). Angiograms identified a complicated lesion or functioning myocardium supplied only by collateral vessels as possible sources of transient ischemia in 73% of noninducible sudden death patients and in 25% of inducible sudden death patients (p = 0.04). Thus coronary angiography in cardiac arrest survivors who do not have inducible ventricular tachycardia often suggests a possible mechanism of transient ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Arrhythmias, Cardiac↗

PubMed1988

Resetting of ventricular tachycardia: implications for localizing the area of slow conduction.

Analysis of local endocardial electrograms recorded during reentrant ventricular tachycardia does not provide direct information as to the participation of the recording site in the tachycardia circuit. To determine if programmed electrical stimulation at the recording site can assist in localizing areas of slow conduction that are participating in the tachycardia circuit, seven patients with sustained monomorphic ventricular tachycardia were studied. The cardiac cycle was scanned with single stimuli delivered during ventricular tachycardia at multiple endocardial sites. In four patients, an endocardial site was identified at which stimuli advanced the tachycardia with marked conduction delay and without alteration of the ventricular activation sequence, as indicated by a lack of change in the configuration of the QRS complex and endocardial electrograms distant from the stimulation site. This finding was seen only during stimulation at sites displaying abnormal electrograms and is consistent with premature depolarization of an area of slow conduction within the tachycardia focus by stimuli delivered at or near that area. Attempted endocardial catheter ablation at or adjacent to these sites in three patients was followed by persistent noninducibility of ventricular tachycardia in one patient, marked modification of the configuration and cycle length of inducible tachycardia in one patient and transient noninducibility of tachycardia in one patient. Programmed electrical stimulation during ventricular tachycardia at sites with abnormal electrograms may provide information about the proximity of the stimulation site to the tachycardia circuit.

Aged↗

PubMed1988

Simultaneous aspergillus endophthalmitis and cytomegalovirus retinitis after kidney transplantation.

We report a case of disseminated and intraocular Aspergillus and cytomegalovirus (CMV) infection in a renal transplant recipient. Aggressive management included reduction of the immunosuppressive medications, systemic and intraocular administration of antifungal agents, treatment with a systemic antiviral drug, and ophthalmic surgery. The clinical and histopathologic features of intraocular Aspergillus and cytomegalovirus infections are discussed. The literature of intraocular mixed opportunistic infections is reviewed.

Adult↗

PubMed1988

Complications of endopyelotomy.

Endopyelotomy is safe with a low risk of complications and a high chance of success given satisfactory percutaneous access to the kidney, adequate incision of the ureteropelvic junction, and proper stenting. The benefits of endopyelotomy are considerable. The postoperative morbidity is much less than that of an open operation, and the technique requires much less time, which may reduce the cost. Furthermore, the ureteral blood supply is undisturbed, which is an important advantage should open pyeloplasty be necessary. Complications of endopyelotomy will be further reduced as urologists gain experience and familiarity with the various endourologic techniques required.

Catheters, Indwelling↗

PubMed1987

Glycolysis preferentially inhibits ATP-sensitive K+ channels in isolated guinea pig cardiac myocytes.

In heart, glycolysis may be a preferential source of adenosine triphosphate (ATP) for membrane functions. In this study the patch-clamp technique was used to study potassium channels sensitive to intracellular ATP levels in permeabilized ventricular myocytes. Activation of these K+ channels has been implicated in marked cellular K+ loss leading to electrophysiological abnormalities and arrhythmias during myocardial ischemia. The results showed that glycolysis was more effective than oxidative phosphorylation in preventing ATP-sensitive K+ channels from opening. Experiments in excised inside-out patches suggested that key glycolytic enzymes located in the membrane or adjacent cytoskeleton near the channels may account for their preference for glycolytic ATP.

Adenosine Triphosphate↗

PubMed1987

Effect of spatial separation of stimulation sites on ventricular refractoriness during programmed electrical stimulation.

To determine if electrical stimulation during the basic ventricular drive train introduces local effects that influence ventricular refractoriness during endocardial stimulation in humans, 10 patients were studied. With a hexapolar catheter with 3 mm interelectrode distances positioned at the right ventricular apex, the ventricular functional and effective refractory periods were determined for unipolar cathodal stimuli of 2 and 5 times diastolic threshold. Stimulation was performed with both the scanning extrastimulus (S2) and basic ventricular drive stimuli (S1) delivered to the same site and to sites separated by 6 mm. The functional refractory period was not changed by delivering the basic drive and extrastimuli to the same as opposed to separate sites (273.5 +/- 16 vs 273.5 +/- 19 msec during stimulation at 2 times threshold and 270 +/- 16 vs 270 +/- 18 msec at 5 times threshold; p = NS). The longest S1-S2 interval at which S2 failed to capture (effective refractory period) was longer by 5.5 +/- 8.2 msec at twice threshold (0.05 less than p less than 0.10) and 5.5 +/- 3.5 msec at 5 times threshold stimulation (p less than 0.01) when the basic drive and extrastimuli were delivered to separate sites. This is consistent with later activation of the extrastimulus sites during the basic drive when the stimulation sites were separate. Thus, with this method of endocardial programmed electrical stimulation, separation of the stimulation sites for the basic drive and extrastimuli does not affect ventricular refractoriness determined by the extrastimulus technique.

Adult↗

PubMed1987

Cardiac ischemia. Part I--Metabolic and physiologic responses.

In the ischemic state, which leads to myocardial infarction, there is a gradation of cardiac muscle injury and a sequence of functional loss. On coronary occlusion an immediate cellular leak of potassium occurs and the rate of relaxation declines. Within 1 to 2 minutes there is complete loss of contraction followed by the onset of contracture in 7 to 10 minutes in isolated preparations. The major problem of this initial period, if the occlusion zone is not too great, is electrical dysfunction. The next 1 to 6 hours is the period of variable reversible injury. Positron emission tomography technique and fatty acid and carbohydrate tracers quantitatively assess regions that are metabolically competent. The problem is to maintain and improve the competence of these regions during reperfusion, whether by thrombolytic therapy (streptokinase) or tissue plasminogen activator, percutaneous transluminal angioplasty, acute coronary artery bypass graft or by total vented bypass and regional reperfusion without thoracotomy (procedure under development).

Animals↗

PubMed1986

Contribution of the anode to ventricular excitation during bipolar programmed electrical stimulation.

Anodal excitation may contribute to the initiation of ventricular arrhythmias during bipolar pacing in the canine ventricle. To determine if anodal excitation occurs during bipolar programmed ventricular stimulation in humans, ventricular electrograms adjacent to the anode and cathode were recorded using a specially designed hexapolar electrode catheter in 10 patients. Single extrastimuli were delivered during ventricular pacing at stimulus strengths slightly above the late diastolic threshold and at 2 to 5 times late diastolic threshold. Evidence of anodal excitation was observed in 18 of the 52 combinations (35%) of stimulus strengths and electrode configurations tested, and occurred in 9 of the 10 patients; it consisted of earliest ventricular activation adjacent to the anode (8 patients) or simultaneous activation at the anode and cathode (3 patients). This occurred either with premature stimuli (3 patients) or during the basic drive and extrastimuli (6 patients). Comparison of local activation times during unipolar pacing supported an anodal contribution to excitation during bipolar pacing and suggested that inhomogenous conduction delays were not responsible for these findings. Thus, anodal excitation occurs frequently during bipolar programmed stimulation and produces marked changes in local myocardial activation, which may potentially influence the initiation of ventricular arrhythmias.

Adult↗

PubMed1986

Comparison of bipolar and unipolar programmed electrical stimulation for the initiation of ventricular arrhythmias: significance of anodal excitation during bipolar stimulation.

To determine if anodal excitation during bipolar stimulation facilitates the initiation of sustained monomorphic ventricular tachycardia, nonsustained polymorphic ventricular tachycardia, or repetitive ventricular responses, both bipolar and cathodal unipolar programmed ventricular stimulation with one to three extrastimuli delivered during ventricular pacing at two rates from the right ventricular apex were performed in 28 patients evaluated for spontaneous sustained ventricular tachycardia or ventricular fibrillation (11 patients), nonsustained tachycardia (eight patients), or syncope (nine patients). In 25 patients a hexapolar pacing catheter was used to record local endocardial activation times adjacent to the cathode and anode and ventricular excitation during bipolar stimulation was defined as predominantly anodal, cathodal, or simultaneous at both anode and cathode. When bipolar and unipolar stimulation were compared there was no difference in the incidence of initiating sustained monomorphic ventricular tachycardia (57% vs 57%), nonsustained polymorphic ventricular tachycardia (14% vs 14%), or repetitive ventricular responses (21% vs 21%), although the response to bipolar vs unipolar stimulation was not concordant in every patient. Evidence of anodal excitation was observed in 11 (44%) patients but did not indicate increased risk of initiation of any ventricular arrhythmia, despite the fact that it was associated with shortening of the ventricular effective refractory period by 5.2 +/- 8.7 msec (p less than .05) during bipolar as opposed to unipolar stimulation. We conclude that unipolar and bipolar stimulation produce a similar incidence of initiation of arrhythmia, despite the frequent occurrence of anodal excitation during bipolar stimulation. Thus, the risk of initiation of nonspecific ventricular arrhythmias during programmed stimulation is unlikely to be reduced by the use of unipolar stimulation.

Adolescent↗

PubMed1985

Importance of internal controls, statistical methods, and side effects in short-term trials of vasodilators: a study of hydralazine kinetics in patients with aortic regurgitation.

We determined that the spontaneous changes in cardiac output (CO) over 12 hr in 21 patients with chronic severe aortic regurgitation averaged +/- 8.9% (p = .03). We then measured changes in CO over time after administering incremental doses of oral hydralazine (50, 100, 150, and 200 mg) every 12 hr and analyzed these changes by several methods. Changes over time of only + 14% were highly significant (p less than .001) when analyzed by t test, but were not significant by repeated-measures analysis of variance (ANOVA). When changes in CO were compared with internal control values (spontaneous changes over 12 hr), only changes of 20% or more were significant (p less than .05). Transient "peak effects" markedly overestimated the maximum effects after all doses. We then compared the incremental doses of hydralazine, given either every 8 or every 12 hr, with respect to (1) the hemodynamic changes induced, and (2) the relative incidence of acute side effects. Maximal increases in CO were similar when hydralazine was given every 8 hr (16 patients) and every 12 hr (21 patients), and ranged from + 14% after 50 mg to + 61% after 200 mg. After the 150 and 200 mg doses, marked sustained increases in CO were present at 8 hr and mild increases in CO were still present at 12 hr. Hydralazine every 8 hr was associated with side effects in 25% to 86% of patients, but when the drug was given every 12 hr it was associated with side effects in only 5% to 19% of patients (p less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗