Natural history and treatment of anorectal strictures complicating Crohn's disease

Forty-four patients seen between 1975 and 1985 with anorectal strictures complicating Crohn's disease have been reviewed to determine the natural history and outcome of surgical treatment. Proctitis was present in 98 per cent, and 93 per cent of patients had sever perianal disease. The site of strictures was rectal in 22, anal in 15 and anorectal in 11 (4 patients had a stricture at 2 sites). Initial treatment was by rectal excision alone in 6, dilatation in 33, and 5 needed no treatment at all. Single dilatation was effective in 15, 8 required two dilatations and in 10 repeated dilatation was necessary. Proctocolectomy was eventually required in 19 patients, 2 have a loop ileostomy and 1 has an ileostomy with a rectal stump in situ. Only 21 remain asymptomatic while 3 continue to need dilatation. Perineal wound healing was delayed in 9 of 19 patients having a proctocolectomy and in 3 the perineal wound has never healed.     

First and Second Generation Lithotripsy in Children: Results, Comparison and Followup

During a 5-year period 32 children and adolescents 4 to 18 years old underwent 35 extracorporeal shock wave lithotripsy (ESWL^* ) treatments for 37 calculi. The unmodified Dornier HM3 lithotriptor was used in 21 cases (60 percent) while the remaining cases were treated with the Siemen Lithostar lithotriptor. The HM3 necessitated general anesthesia in 67 percent of patients and the Lithostar necessitated intravenous sedation in 86 percent. The majority of pediatric lithotripsy treatments were performed on an outpatient basis (24) or during an overnight hospital stay (3) while 8 were done on an inpatient basis. Of the 37 stones treated with 1 ESWL session 68 percent resolved, 19 percent had residual fragments less than 4 mm., 8 percent had residual fragments greater than 4 mm. and 5 percent required an endoscopic procedure for resolution. When success rates by lithotriptor were examined no significant difference between the 2 machines was identified although the HM3 treated larger stones (p = 0.0499). There were no statistical differences in regard to success and the use of stents, patient age or stone location between the 2 lithotriptors. Three patients required adjuvant procedures, and complications and morbidity developed in 2 and 5, respectively. All children or parents were contacted for followup (range 7 to 67 months). One child required ESWL for a new stone while another passed a stone without intervention. Only 1 child with a residual fragment less than 4 mm. became symptomatic but needed no intervention while 1 of 3 with fragments greater than 4 mm. needed intervention. No patients required open or percutaneous intervention.     

Neuronal vacuole formation in the rat posterior cingulate/retrosplenial cortex after treatment with the N-methyl-d-aspartate (NMDA) antagonist MK-801 (dizocilpine maleate)

Cytoplasmic vacuoles appear in neurons of the posterior cingulate/retrosplenial cortex (PC/RS) of rats after treatment with N-methyl-d-aspartate (NMDA) receptor antagonists. Prominent dilatation of mitochondria and endoplasmic reticulum has been described within 2 h; however, the ultrastructural features of vacuole formation are unknown. To investigate this, the present study examined the PC/RS cortex of male rats (age 60–70 days) at 15, 30, 45, 60, 90, and 120 min after subcutaneous treatment with 1 mg/kg of the noncompetitive NMDA antagonist MK-801 (dizocilpine maleate, 5-methyl-10, 11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine). Subtle mitochondrial dilatation was identified in a few neurons as early as 15 min postdose (MPD). By 30 MPD, dilatation was more pronounced in mitochondria and also involved the endoplasmic reticulum and perinuclear space. Ribosomal disaggregation and degranulation were also evident by 30 MPD. At all subsequent time points, dilatation of mitochondria and endoplasmic reticulum progressed in severity. Although the relative involvement of mitochondria and endoplasmic reticulum varied, glia were not involved. These ultrastructural data suggest that after treatment with MK-801, mitochondrial dilatation precedes involvement of endoplasmic reticulum in vacuolization of susceptible PC/RS cortical neurons. The early mitochondrial effects identified in this study suggest an initial metabolic insult that rapidly progresses to affect endoplasmic reticulum and ribosomes. This strengthens the relationship between the ability of certain NMDA antagonists to induce energy perturbations and neuronal vacuoles in the same region of the rat cerebral cortex.     

Effects of angiotensin converting enzyme inhibition in adult polycystic kidney disease.

The pathogenesis of hypertension in autosomal-dominant polycystic kidney disease (ADPKD) is unclear, but increased activity of the renin-angiotension system may contribute. The renal and systemic hemodynamic response to lisinopril, an angiotension converting enzyme (ACE) inhibitor, in patients with ADPKD without renal failure was compared with the response in matched unaffected family members. Mean blood pressure and renal vascular resistance decreased in the affected group after lisinopril, with no significant change in the unaffected group. Glomerular filtration rate (GFR) was unchanged and therefore filtration fraction fell significantly. Changes in urinary excretion of 6-keto-PGF1 alpha and kallikrein suggested that increased renal synthesis of PGI2 or activation of the renal kallikrein-kinin system were not likely to be responsible for the hemodynamic effects. The acute decrease in renal vascular resistance without change in GFR suggests that ACE inhibition may have a particular value in the treatment of hypertension associated with ADPKD which should be assessed by further long-term studies.     

The “suffocation alarm” theory of panic attacks: A critical commentary

In 1993 Klein proposed a “false suffocation alarm” theory of panic attacks, claiming that many spontaneous panic attacks are due to a “suffocation monitor” in the brain erroneously signaling a lack of useful air, and triggering an evolved “suffocation alarm system”. He proposed that carbon dioxide acts as a panic stimulus because rising arterial CO₂ suggests suffocation may be imminent. The present paper provides a critical analysis of Klein's theory and concludes that there is neither empirical evidence nor compelling argument to support the assumptions or the proposed neurological mechanism of a “suffocation alarm”, true or false, or a CO₂ “suffocation monitor”. Data relevant to the role of breathing in the phenomenon of panic can be parsimoniously subsumed within the domain of dyspnea.     

Adenylate cyclase activity as a predictor of thyroid tumor aggressiveness

Prior studies in our laboratory have shown that human thyroid neoplasms have a greater adenylate cyclase activity in response to thyroid stimulating hormone (TSH) than does the adjacent histologically normal thyroid tissue. However, there is little information relating activity of the TSH receptor-adenylate cyclase system to the type of thyroid neoplasm. Thyroid tissue from 67 patients was divided by clinical and histological criteria into 6 categories: normal (59), benign tumors (20), stage 1 carcinoma—intrathyroidal involvement only (25), stage 2 carcinomaregional lymph node involvement (6), stage 3 and 4 carcinoma—tissue invasion or distant metastasis (11), and medullary carcinoma (3). Adenylate cyclase activity in an 8,000 x g thyroid membrane preparation was determined in the basal state and when maximally stimulated with 300 mU/ml TSH. The cyclase responsiveness was the ratio of TSH stimulated adenylate cyclase activity compared to basal adenylate cyclase activity. The cyclase responsiveness by category is: normal, 2.8±0.2 (mean ± SEM); benign, 17.9±2.4; stage 1 carcinoma, 9.2±1.9; stage 2 carcinoma, 4.0±1.0; stage 3 and 4 carcinoma, 1.6±0.4; and medullary carcinoma, 1.05±0.04 (for the neoplasms,p <0.02 by ANOVA). Tumor stage was the only correlate with this trend as other prognostic risk factors (age, sex, a history of neck irradiation, or papillary versus follicular histology) showed no difference in cyclase responsiveness. These studies demonstrate a consistent inverse correlation between adenylate cyclase responsiveness and tumor stage or aggressiveness. Cyclase responsiveness appears to have clinical application for predicting which thyroid tumors will behave aggressively.

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Resumen Estudios previos en nuestro laboratorio han demostrado que los neoplasmas tiroideos humanos poseen una mayor actividad de adenilato ciclasa en respuesta a la administración de hormona estimulante de la tiroides (TSH) que el tejido tiroideo histológicamente normal adyacente. Sin embargo, existe muy poca información sobre la relation de la actividad del sistema receptor de TSH-adenilato ciclasa y el tipo del neoplasma tiroideo. Tejido tiroideo proveniente de 67 pacientes fue dividido mediante criterios chlínicos e histológicos en 6 categorias: normal (59), tumores benignos (20), extensión intratiroidea solamente en estado 1 (25), carcinoma-extensión ganglionar regional en estado 2 (6), carcinoma-invasión tisular o metástasis distantes en estados 3 y 4 (11), y carcinoma medular (3). La actividad de la adenilato ciclasa en una preparación de membrana tiroidea de 8,000 × g fue determinada en el estado basai y en estado de maxima estimulación con 300 mU/ml TSH. El grado de respuesta de la ciclasa fue la tasa de actividad de la adenilato ciclasa estimulada por TSH comparada con la actividad basai de la adenilato ciclasa. El grado de respuesta por categorías fue: normal, 2.8±0.2; tumor benigno, 17.9±2.4; carcinoma estado 1, 9.2±1.9; carcinoma estado 2, 4.0±1.0; carcinoma estados 3 y 4, 1.6±0.4; y carcinoma medular, 1.05±0.04 (para los neoplasmas,p < 0.02 por ANOVA). El estado del tumor apareció como el único factor de correlatión con esta gradación, ya que otros factures de pronóstico (edad, sexo, historia de irradiación cervical, histología papilar versus folicular) no demostraron diferencia en cuanto al grado de respuesta de la ciclasa. Estos estudios demuestran una consistente relación inversa entre el grado de respuesta de la adenilato ciclasa y el estado o agresividad tumoral. El grado de respuesta de la ciclasa parece tener aplicación clínica para predecir qué tumores tiroideos se habrán de comportar en forma agresiva.

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Résumé Les études antérieures provenant de nos laboratoires ont démontré une augmentation de l'activité enzymatique de l'adénylate-cyclase en réponse à la thyroïd stimulating hormone (TSH) dans le tissu thyroïdien humain tumoral, par rapport au tissu thyroïdien adjacent normal. Cependant il existe peu de données concernant l'activité du système récepteur TSH/adénylatecyclase par rapport au type de tumeur de la thyroïde. Les tissus thyroïdiens provenant de 67 patients différents ont été repartis en 6 groupes selon des critères cliniques et histologiques: normal (59), tumeur bénigne (20), cancer stade 1 (intrathyroïdien uniquement) (25), cancer stade 2 (envahissement ganglionnaire régional) (6), cancer stade 3 et 4 (envahissement tissulaire avoisinant ou métastases à distance (11), et cancer médullaire (3). A partir d'une préparation de membrane thyroïdienne centrifugée à 8,000 × g, l'activité de l'adénylate-cyclase a été déterminée en l'état basai et après stimulation maximale par 300 mU/ml de TSH. La réponse enzymatique a été mesurée comme étant le rapport de l'activité stimulée par la TSH/activité basale. Les résultats selon les 6 groupes étaient (moyen±ET): tissu normal, 2.8±0.2; tumeur bénigne, 17.9±2.4; cancer stade 1, 9.2±1.9; cancer stade 2, 4.0±1.0; cancers stade 3 et 4, 1.6±0.4; et cancer médullaire, 1.05±0.04 (p < 0.02 par l'analyse de variance pour les néoplasies). Le stade tumoral était la seule variable corrélée avec l'activité enzymatique. L'activité enzymatique n'était pas corrélée avec l'âge, le sexe, les antécédents d'irradiation cervicale antérieure ou l'histologie (papillaire vs. folliculaire). Ces études montrent un rapport inversement proportionnel entre l'activité d'adénylate-cyclase et le degré d'agressivité tumorale ou le stade. La réponse d l'adénylate-cyclase paraît avoir une application clinique: prévoir quelles tumeurs thyroïdiennes auront une évolution agressive.

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Presented at the International Association of Endocrine Surgeons in Sydney, Australia, September, 1987.

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Supported in part by the Medical Research Service of the Veterans Administration.     

Membrane-coated fiber array approach for predicting skin permeability of chemical mixtures from different vehicles.

A membrane-coated fiber (MCF) array approach was developed for quantitative assessment of skin absorption from chemical mixtures, which was based on the similarity in the absorption mechanisms of the MCF membrane and the stratum corneum of the skin. A set of probe compounds were used to detect the relative molecular interaction strengths of chemicals with the vehicle and the membranes, which provided a linkage between the skin permeability (log k) and MCF partition coefficients (log KF). A predictive model was established via multiple linear regression analysis of the data matrix of experimentally measured log k value and log KFm values; log k=a0+a1 log KF1+a2 log KF2+...+an log KFm, where m is the number of diverse MCFs. Twenty-five probe compounds and three MCFs (polydimethylsiloxane for lipophilic, polyacrylate for polarizable, and CarboWax for polar interactions) were used to demonstrate the model development processes in the MCF array approach. The skin permeability of the probe compounds was measured with conventional diffusion cell experiments using dermatomed porcine skin. Three predictive models were established for skin permeability prediction from chemical mixtures in water, 50% ethanol, and 1% sodium lauryl sulfate (SLS) with R2 values of 93, 91, and 83, respectively. The log k and log KF values were considerably altered by the addition of ethanol or SLS into the dose vehicle; however, their correlations to skin permeability remained strong under various conditions. These results suggested that the experimentally based MCF array approach can be used to predict skin absorption from chemical mixtures in different vehicles or formulations.     

18F-FDG assessment of glucose disposal and production rates during fasting and insulin stimulation: a validation study.

The glucose analog (18)F-FDG is commonly used to quantify regional glucose uptake in vivo. The aim of this study was to test whether the analysis of plasma (18)F-FDG kinetics could be used to estimate endogenous glucose production (EGP) and the total rate of appearance (Ra), total rate of disappearance (Rd), and the metabolic clearance rate (MCR) of glucose. METHODS: Fourteen pigs were coinjected with (18)F-FDG and 6,6-(2)H-glucose ((2)H-G) during fasting (n = 6) and during physiologic (1.0 mU.kg(-1).min(-1), n = 4) and supraphysiologic (5.0 mU.kg(-1).min(-1), n = 4) euglycemic hyperinsulinemia. Arterial plasma was sampled for 180 min to quantify the parameters for the 2 tracers. RESULTS: Fasting Rd((2))(H-G) and Rd(FDG) were 12.3 +/- 2.1 and 13.3 +/- 1.3 micromol.kg(-1).min(-1) (difference not statistically significant [NS]). M values were more than doubled between the 2 clamp studies (P < 0.0001). Rd((2))(H-G) and Rd(FDG) were dose-dependently higher during the hyperinsulinemic state (19.8 +/- 3.7 vs. 18.9 +/- 1.1 and 31.4 +/- 4.1 vs. 31.9 +/- 2.3 in 1.0 and 5.0 mU.kg(-1).min(-1) studies, respectively; difference between tracers NS) than during the fasting state, with a parallel suppression of EGP((2))(H-G) and EGP(FDG). Parameters estimated by (18)F-FDG and (2)H-G were equivalent in all groups; their agreement was confirmed by Bland-Altman examination. Total Rd(FDG) correlated with Rd((2))(H-G) (r = 0.74; P = 0.003), M (r = 0.92; P = 0.001), MCR((2))(H-G) (r = 0.52; P = 0.037), and EGP((2))(H-G) (r = -0.71; P = 0.004). EGP(FDG) correlated with EGP((2))(H-G) (r = 0.62; P = 0.018), Rd((2))(H-G) (r = -0.78; P = 0.001), and MCR((2))(H-G) (r = -0.67; P = 0.008). The (18)F-FDG mean transit time correlated inversely with the M and Rd values and positively with EGP. CONCLUSION: The glucose analog (18)F-FDG can be used in the simultaneous estimation of whole-body glucose turnover and production and regional (18)F-FDG PET measurements under both fasting and insulin-stimulated conditions.