Immunohistochemistry of anterior proliferative vitreoretinopathy

Anterior proliferative vitreoretinopathy is characterized by epiretinal proliferation that extends anteriorly over the vitreous base, and may, in addition to the cells usually contributing to proliferative vitreoretinopathy, also contain cells of ocular structures located in that area. We examined 11 complete globes with aPVR that were enucleated after previous severe trauma or perforating injuries (n=8) and complicated retinal detachment (n=3) by a panel of immunohistochemical markers. We found presence of RPE, glial cells, macrophages and fibrocytes, as consistently reported in PVR membranes. In addition, T-cell lymphocytes were present in 6 of the cases, and cells expressing the common leucocyte antigen on 8 cases. Cells staining positive for the intracytoplasmic contractile filament-smooth muscle actin were present in 5 cases and cells staining for desmin in one case. Collagen type IV was part of most of the membranes, and vessels with leakage of plasma factors were present in more than half of the cases.This paper was presented in part at the First Annual Meeting of the European Community Ophthalmic Research Association (ECORA), Bonn, Germany, 6.10.1993.     

Presynaptic α2A-adrenoceptors inhibit the release of endogenous dopamine in rabbit caudate nucleus slices

₂-Adrenoceptors modulating the release of dopamine were identified and characterized in slices of the head of the rabbit caudate nucleus. Release of endogenous dopamine was measured by fast cyclic voltammetry as the increase in the extracellular concentration of dopamine elicited by electrical stimulation. The electrochemical signal was identified as dopamine by means of the oxidation potential, the voltammogram and the fact that the signal was not changed by desipramine, which inhibits the high affinity uptake of noradrenaline, but was greatly increased by nomifensine, which in addition inhibits the high affinity uptake of dopamine.Stimulation by 6 pulses/100 Hz increased the extracellular concentration of dopamine by about 85 nM. The selective ₂-adrenoceptor agonist 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) reduced this release with an EC₅₀ of 173 nM and by maximally 75%. The ₂-adrenoceptor agonists clonidine and oxymetazoline only tended to cause a decrease. Six drugs, including oxymetazoline, were tested as antagonists against UK 14,304. Their order of antagonist potency (pK_D values in brackets) was rauwolscine (8.0) > oxymetazoline (7.5) > 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101; 7.3) > phentolamine (7.1) > corynanthine (5.1) prazosin (< 6). Given alone, the antagonists did not change the release of dopamine elicited by 6 pulses/100 Hz, and the same was true for the dopamine receptor antagonist sulpiride. When caudate slices were stimulated by 10 pulses/1 Hz, sulpiride increased the release of dopamine. Desipramine and rauwolscine, in contrast, again caused no change.It is concluded that dopaminergic axons in the rabbit caudate nucleus possess release-inhibiting ₂-adrenoceptors. The antagonist affinities indicate that they belong to the _2A subtype. In this, they agree with all presynaptic ₂-autoreceptors studied so far in rabbits as well as with the ₂-heteroreceptors modulating the release of serotonin in rabbit brain cortex, suggesting that at least the majority of presynaptic ₂-adrenoceptors in the rabbit are _2A. The agonist sensitivity of the caudate presynaptic ₂-adrenoceptors is low in comparison with cerebrocortical presynaptic ₂-autoreceptors, possibly due to absence of a receptor reserve. Correspondence to: N. Limberger at the above address     

Behavioral and autonomic responses to intermittent social stress: differential protection by clonidine and metoprolol

The present study investigated physiological and pharmacological characteristics of socially stressed animals. Specifically, we examined (1) to what degree autonomic and behavioral stress reactions during intermittent confrontations between an intruder male adult Long-Evans rat with an aggressive resident undergo habituation, and (2) to what extent the defeat-experienced animal can be protected against these stress reactions with clonidine or metoprolol, two adrenergic agents with clinical anxiolytic effects. We developed an acute social stress situation that consisted of initially placing an experimental rat as an intruder into the homecage of a resident while the resident was not present, thereafter permitting brief physical agonistic interactions with the reintroduced resident until the intruder was forced into a submissive supine posture and emitted ultrasonic vocalizations (USV), and eventually exposing the intruder to the resident's threats for one hour, while being shielded from potentially injurious attacks (threat encounter). Over the course of the initial 4-weekly threat encounters the acute tachycardia but not the hyperthermic stress responses decreased in magnitude. Following the first three threat encounters core temperature (T_c) was significantly elevated for at least 3 h. The T_c was already elevated when the repeatedly defeated intruder was confronted with the olfactory cues of the resident's cage. This conditioned anticipatory hyperthermia developed in the course of the first three confrontations and was paralleled by a decrease in exploratory and motor behavior and by an increase in defensive behaviors and in both types of USV emitted in the low (20–30 kHz) and the high (31–70 kHz) frequency range. Clonidine (0.01–0.1 mg/kg, IP), an ₂-adrenergic agonist and metoprolol, a -adrenergic blocker (1.0–10.0 mg/kg, IP), dose-dependently prevented the tachycardic response to stress. Only clonidine, but not metoprolol, also attenuated the rise in T₀ during the 1-h agonistic interaction. Clonidine decreased those aspects of motor behavior (e.g. rearing, walking) that are of lesser cost for the individual but maintained high levels of defensive reactions and increased the duration of low USV. The high doses of clonidine (0.06, 0.1 mg/kg) attenuated the homeostatic regulation and sedated the intruder while exposed to threats during a social confrontation. The absence of attenuation of the high level of defensive behavior and the prolonged low USV suggest a stress intensification by the higher doses of clonidine. In conclusion, after the fourth encounter, the autonomic, behavioral and vocal response pattern prior to and during repeated weekly confrontations show no evidence for habituation for the following 6 weeks. Moreover, adrenergic therapeutic agents that are applied to treat symptoms of anxiety block the tachycardic response but may actually intensify defensive behavior and certain stress vocalizations.     

Treatment of systemic and renal-limited vasculitic disorders with pooled human intravenous immune globulin

Idiopathic crescentic glomerulonephritis is characterized by an absence of immunohistological evidence of immune deposits, often with evidence of segmental glomerular necrosis. Such pauciimmune crescentic glomerulonephritis is the most common renal manifestation seen in patients with Wegener's granulomatosis, polyarteritis nodosa, and glomerulonephritis associated with other systemic vasculitic disorders (i.e., Churg-Strauss syndrome). Recently, the idiopathic crescentic glomerulonephritides, either in renal-limited form or in association with other systemic vasculitic disorders, were found to have in common a serologic marker, antineutrophil cytoplasmic autoantibodies. These cytoplasmic and perinuclear antineutrophil cytoplasmic autoantibodies are specific for constituents of neutrophil primary granules and monocyte lysosomes. As serologic markers for vasculitic disorders, they are also felt to be directly involved in the pathogenesis of necrotizing vascular injury.In vitro, both perinuclear and cytoplasmic antineutrophil cytoplasmic autoantibodies are capable of causing cytokineprimed neutrophils to undergo degranulation and respiratory burst, releasing toxic oxygen species and lytic enzymes. Antiidiotype antibodies which inhibit antineutrophil cytoplasmic autoantibodiesin vitro, in a V region-dependent manner, are found in pooled humanγ-globulin preparations. Intravenous immune globulin infusionsin vivo have produced dramatic improvements in the necrotizing vascular injury produced by antineutrophil cytoplasmic autoantibodies, and a rapid reduction in these autoantibody levels is seen post-intravenous immune globulin infusion in most patients. The proposed mechanisms of action of intravenous immune globulin in vasculitic disorders include Fc-dependent mechanisms, and F(ab′)₂-dependent mechanisms are likely important. Intravenous immune globulin infusions appear to have an important place in the management of the necrotizing vascular injury. Blinded, randomized, placebo-controlled trials will be necessary to establish definitively intravenous immune globulin as a therapeutic option in vasculitic disorders.     

Functional consequences of inhibition of nucleotide breakdown in rat vas deferens: a study with Evans blue

The effect of Evans blue on nucleotide breakdown, nucleotide-evoked contractions and electrically evoked contractions, overflow of ATP and overflow of tritium (after labelling with [³H]-noradrenaline) was studied in rat vas deferens. Pieces of vas deferens degraded 83 to 85% of added ATP, ADP and 2-methylthio ATP (all 100 M) over 30 min. Evans blue (100 M) reduced this degradation to 22 to 26%. Nucleotides elicited contraction with potency declining in the order , \-methylene ATP > 2-methylthio ATP > ATP > ADP. Evans blue (100 M) shifted the concentration-response curve of , \-methylene ATP to the right and increased the maximum. Concentration-response curves of ATP, ADP and 2-methylthio ATP, in contrast, were shifted to the left and responses were much potentiated. In the presence of Evans blue, the rank order of potency was ATP > 2-methylthio ATP > , \-methylene ATP > ADP. Electrical field stimulation (100 pulses at 10 Hz) elicited contraction and an overflow of tritium and ATP. Evans blue (100 M) did not alter the contraction and the evoked overflow of tritium but increased 24-fold the evoked overflow of ATP. The results indicate that Evans blue may serve as an — albeit impure — ecto-nucleotidase inhibitor in functional experiments. Such experiments demonstrate that the low potency of ATP (and also ADP and 2-methylthio ATP) in eliciting contraction, and the small size of the overflow of ATP upon sympathetic nerve stimulation, are due to rapid breakdown.     

Electrocardiological profile and proarrhythmic effects of quinidine,verapamil and their combination: a mapping study

Quinidine and verapamil are widely used as antiarrhythmic agents and their combination is often used in the treatment of supraventricular tachycardia. This study was undertaken to clarify, whether these drugs exert proarrhythmic effects on the ventricles in therapeutic concentrations and whether possible arrhythmogenic effects might be enhanced by combination. Isolated rabbit hearts perfused according to the Langendorff technique were treated with increasing concentrations of quinidine (0.05 to 3.5 M) or verapamil (5 to 50 M) or of their combination (70:1 or 10:1; quinidine:verapamil) corresponding to common low, medium and high free therapeutic concentrations. The epicardial activation process was measured using a computer assisted mapping system for unipolar multichannel recording (256 channels simultaneously).Both substances prolonged the atrioventricular conduction time PQ. This effect was even more pronounced if the 70:1 combination was administered. The activation pattern was altered by both drugs and their combination to the same extent as became obvious from analysis of local activation vectors and of localisation of breakthroughpoints of epicardial activation for heart beats under control conditions and under drug treatment. The epicardial potential durations were prolonged by quinidine and to the same degree by the combinations, but not by verapamil alone. The total activation time was prolonged under the influence of quinidine and if the 70:1 combination was given. Both substances exerted a negative inotropic effect which was enhanced in an additive manner if both drugs were combined. In parallel the coronary flow was diminished.From these results it is concluded that (1) in this therapeutic concentration range quinidine possess a greater proarrhythmic risk than verapamil, (2) that both drugs' PQ prolonging effect can be enhanced by combination, (3) that combination does not enhance the proarrhythmic effects but the negative inotropic effects.     

Cardiovascular effects of agmatine,a “clonidine-displacing substance”, in conscious rabbits

Agmatine has been identified as a clonidine-displacing substance in extracts from bovine brain. We studied its effect on cardiovascular regulation and the role played in this effect by ₂-adrenoceptors.In conscious rabbits, agmatine 10 g kg^–1 injected intracisternally (i.e.) caused no change, whereas agmatine 30, 100 and 300 g kg^–1 i.e. increased renal sympathetic nerve firing, the plasma concentration of noradrenaline and adrenaline and arterial blood pressure. Heart rate tended to be decreased. Yohimbine 1.5 g kg^–1 i.e. caused no change, whereas yohimbine 5, 15 and 50 g kg^–1 increased renal sympathetic nerve activity, the plasma concentration of noradrenaline and adrenaline, blood pressure and heart rate. In rabbit brain cortex slices preincubated with [³H]-noradrenaline, agmatine 1 to 100 M did not modify the electrically evoked overflow of tritium (either 4 pulses at 100 Hz or 36 pulses at 3 Hz). The evoked overflow was reduced by 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline (UK 14304) 0.03 to 30 nM (4 pulses at 100 Hz), and this inhibition was not affected by agmatine 10 and 100 M. Agmatine did not change the basal efflux of tritium.The results show that agmatine, like yohimbine, causes central sympathoexcitation when given i.e., but agmatine differs from yohimbine in that it does not increase heart rate. Agmatine acts neither as an agonist nor as an antagonist at the ₂-autoreceptors in rabbit brain cortex. ₂-Adrenoceptors, therefore, are probably not involved in its cardiovascular effects. An action at imidazoline receptors in the medulla oblongata or some other hitherto unknown mechanism may be responsible for the sympathoexcitation.     

Analysis of receptor-G protein interactions in permeabilized cells

Receptor-induced binding of the stable GTP analogue, guanosine 5-[-thio]triphosphate (GTP [S]), to guanine nucleotide-binding regulatory proteins (G proteins) was measured in various permeabilized cells. In myeloid differentiated human leukemia (HL-60) cells, permeabilized with either digitonin, streptolysin O or Staphylococcus aureus -toxin, binding of GTP [S] induced by three distinct chemoattractant receptors was observed. The extent of receptor-stimulated GTP [S] binding (maximally about 2-fold) was independent of the type of permeabilizing agent used. In human erythroleukemia cells permeabilized with digitonin, agonist activation of thrombin and neuropeptide Y receptors increased GTP [S] binding by 1.8- and 1.5-fold, respectively. Finally, in adherently grown human embryonic kidney cells permeabilized with digitonin, activation of the stably expressed human muscarinic m3 receptor increased GTP[S] binding by about 1.6-fold. In digitonin-permeabilized HL-60 cells, a quantitative analysis of formyl peptide receptors and interacting G proteins was performed. About 50,000 formyl peptide receptors per cell were detected. Agonist binding to these receptors was fully sensitive to regulation by guanine nucleotides and pertussis toxin. The number of high-affinity GTP [S] binding sites, most likely representing heterotrimeric G proteins, was calculated to be about 670,000 per cell. Stimulation of formyl peptide receptors led to the activation of about 130,000 of high-affinity GTP [S] binding sites, indicating a ratio of about three activated G proteins per one agonist-activated receptor.Overall, this study indicates that receptor-stimulated GTP [S] binding to G proteins in permeabilized cells is a sensitive and rapid method for analyzing receptor-G protein interactions, which can be applied to a variety of cultured cells and for various receptor systems.     

Reconstruction after gastrectomy and quality of life

To evaluate quality of life and functional results following surgery for gastric cancer we studied 104 patients with no evidence of disease at a minimum of 12 months postoperatively. Patients were treated with total gastrectomy and jejunal pouch reconstruction according to Hunt-Lawrence-Rodino (n=59) or simple esophagojejunostomy (n=24) and distal subtotal gastrectomy (n=21). No significant differences were found between total gastrectomy with pouch reconstruction and distal gastric resection with respect to dumping or heartburn, whereas patients with total gastrectomy and restoration with esophagojejunostomy suffered from both. The latter group of patients also had reduced nutritional status. Although there is a lack of a proper definition of quality of life, all instruments applied to its measurement indicated improved results for patients with pouch reconstruction and those after distal gastrectomy, but we could not state any significant differences. We conclude that in terms of postoperative functional results as well as quality of life distal gastric resection has no advantage over total gastrectomy with pouch reconstruction; hence a reduction of surgical radicality in an attempt to improve postoperative results is not justified. Pouch reconstruction should be considered the treatment of choice for reconstruction after total gastrectomy.

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Resumen Con miras a evaluar la calidad de la vida y los resultados funcionales luego de cirugía por cáncer gástrico, estudiamos 104 pacientes que se encontraban libres de enfermedad a un mínimo de 12 meses postoperatorios. Los pacientes fueron tratados con gastrectomía total y reconstrucción con una bolsa yeyunal de tipo Hunt-Lawrence-Rodino (n=59) o simple esofagoyeyunostomía (n=24) y gastrectomía subtotal distal (n=21). No se encontraron diferencias significantivas entre los pacientes sometidos a gastrectomía total con reconstrucción con bolsa yeyunal y los sometidos a resección distal con respecto a dumping o pirosis, en tanto que los pacientes sometidos a gastrectomía total y restauración mediante esofagoyeyunostomía exhibieron ambos síntomas. Además, los últimos desarrollaron deterioro de su estado nutricional. Aparte de la falta de una adecuada definición de calidad de la vida, todos los parámetros aplicados para su medición demostraron mejores resultados en los casos de gastrectomía total con reconstrucción con bolsa yeyunal y en los casos de gastrectomía distal, pero sin que pudiéramos hallar diferencias significativas. Nuestra conclusión es que en términos de los resultados funcionales postoperatorios así como de calidad de la vida, la resección gástrica distal no tiene ventaja sobre la operación con reconstrucción con bolsa yeyunal y que no se justifica una reducción de la radicalidad quirúrgica con el objeto de mejorar los resultados postoperatorios. La reconstrucción con bolsa yeyunal debe ser considerada como el procedimiento de elección en la gastrectomía total.

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Résumé Afin d'évaluer la qualité de vie et les résultats fonctionnels après chirurgie pour cancer gastrique, nous avons étudié 104 patients qui semblaient guéris à 12 mois. Les patients ont eu soit une gastrectomic totale suivie ou de la confection d'un néogastre jéjunal selon le procédé de Hunt-Lawrence-Rodino (n=59) ou une simple anastomose oesojéjunale (n=24), soit d'une gastrectomie distale subtotale (n=21). Il n'y avait aucune différence significantive entre la gastrectomie totale suivie de reconstruction par néogastre et la gastrectomie distale subtotale en ce qui concerne le dumping syndrome ou le reflux, alors que les patients qui avaient eu une gastrectomie totale suivie d'anastomose oesojéjunale avaient les deux. Chez ces derniers, on a également noté une certaine malnutrition. En dépit du manque de définition précise de la qualité de vie, tous les moyens utilisés pour la mesurer ont indiqué um meilleur résultat pour les patients ayant eu une reconstruction avec néogastre par rapport à la gastrectomie distale, sans toutefois atteindre la signification statistique. Nous concluons qu'en terme de résultats fonctionnels postopératoires ainsi que de la qualité de vie, la gastrectomie distale ne présente aucun avantage par rapport à la gastrectomie totale suivie de néogastre, et une réduction dans l'importance de l'intervention pour améliorer les résultats fonctionnels n'est pas justifiée. La confection d'un néogastre doit être la méthode de reconstruction de choix après gastrectomie totale.

     

The Burden of Obesity and Its Sequelae

Obesity [body mass index (BMI) ≥30 kg/m²] is common in many parts of the world, especially in the established market economies, formerly socialist economies of Europe and Latin America and the Caribbean, as well as the Middle Eastern Crescent. Worldwide, as many as 250 million people may be obese (7% of the adult population) and 2 to 3 times as many may be considered overweight (BMI 25 to 30 kg/m²). The prevalence of obesity seems to be increasing in most parts of the world, even in areas where obesity used to be rare.A waist circumference greater than 102cm in men and 88cm in women may be a more sensible classification than BMI to identify individuals who are at increased health risk because of obesity, but information on this point is still scarce.Increased fatness measured by a high BMI, large waist circumference or high waist/hip circumference ratio is associated with many chronic diseases as well as poor physical functioning. These all contribute to the costs associated with excess bodyweight. The economic costs of obesity can be broken down into 3 levels Direct costs: costs to the community related to the diversion of resources to the diagnosis and treatment of diseases directly related to obesity as well as the treatment of obesity itself. These costs have been estimated to account for 2 to 8% of total healthcare costs of various countries. Indirect (or societal) costs: these costs are related to the loss of productivity caused by absenteeism and premature death and disability pensions. There is a lack of good economic analysis in this area, although research from Sweden, Finland and The Netherlands has clearly shown that obesity is associated with increased sick leave and the need for disability pensions. Personal costs: obese individuals may earn less than their lean counterparts because of job discrimination (related to the stigma associated with obesity or because of diseases and disabilities caused by obesity). Many insurance companies (particularly life insurance) charge higher premiums with increasing degrees of overweight.In conclusion, there is much indirect information that obesity and overweight are important and growing public health concerns that contribute substantially to healthcare-related costs. Effective strategies for the prevention and management of obesity are needed.