Classical and recent advances in the treatment of inflammatory bowel diseases.

Crohn's disease (CD) and ulcerative colitis (UC) are intestinal disorders that comprise the inflammatory bowel diseases (IBD). These disorders have a significant effect on the quality of life of affected patients and the increasing number of IBD cases worldwide is a growing concern. Because of the overall burden of IBD and its multifactorial etiology, efforts have been made to improve the medical management of these inflammatory conditions. The classical therapeutic strategies aim to control the exacerbated host immune response with aminosalicylates, antibiotics, corticosteroids, thiopurines, methotrexate and anti-tumor necrosis factor (TNF) biological agents. Although successful in the treatment of several CD or UC conditions, these drugs have limited effectiveness, and variable responses may culminate in unpredictable outcomes. The ideal therapy should reduce inflammation without inducing immunosuppression, and remains a challenge to health care personnel. Recently, a number of additional approaches to IBD therapy, such as new target molecules for biological agents and cellular therapy, have shown promising results. A deeper understanding of IBD pathogenesis and the availability of novel therapies are needed to improve therapeutic success. This review describes the overall key features of therapies currently employed in clinical practice as well as novel and future alternative IBD treatment methods.

Mechanisms of pulmonary vasoconstriction and bronchoconstriction produced by PAF in the guinea-pig: role of platelets and cyclo-oxygenase metabolites.

1. The mechanisms of action of platelet activating factor (PAF) in the bronchial and cardiovascular systems have not yet been fully elucidated. In order to characterize better and to ascertain whether the effects of PAF in both these systems may be ascribed to the same mechanisms, we examined the actions of PAF in the heart-lung preparation of guinea-pig (HLP). The role of platelets and of cyclo-oxygenase metabolites was investigated. 2. In HLPs perfused with autologous blood, bolus injections of PAF (4-32 ng) produced major effects at the pulmonary vascular and bronchial levels. Both dose-related pulmonary vascular hypertension and bronchoconstriction produced by PAF were diminished to the same extent (46% and, respectively, 47%) when HLPs were perfused with a medium consisting of homologous red blood cells suspended in physiological solution containing 3.5% dextran (RBC). This suggests that the effects of PAF partially depend on the presence of formed elements. 3. When indomethacin (30 microM) was added to the perfusing blood, the dose-response curve for the pulmonary hypertensive responses produced by PAF was strongly reduced (90%) in comparison to control preparations, whereas the bronchoconstrictor effects of PAF were only partially diminished (23%). These data constitute direct evidence that products of the cyclo-oxygenase pathway exert a major role in the vascular, rather than in the bronchial actions of PAF. 4. In HLPs perfused with RBC containing indomethacin (30 microM), the pulmonary vascular hypertensive responses produced by PAF were almost completely abolished, thus indicating that cyclo-oxygenase products from tissues are involved in these effects. Conversely, PAF administration continued to cause dose-related bronchoconstrictor responses that were reduced only partially in comparison with HLPs perfused with RBC in the absence of the cyclo-oxygenase inhibitor. This implies that PAF also has direct action on the bronchoconstriction evoked.5. At the cardiac level, administration of PAF in HLPs perfused with blood caused a dose-related increase in right atrial pressure accompanied by a decrease in left atrial pressure and cardiac output,which were completely suppressed or attenuated by the absence of formed elements and the addition of indomethacin. This suggests that the progressive heart impairment is secondary to the severe pulmonary hypertension induced by PAF.6. The results of this study performed in the heart-lung preparation of the guinea-pig, which made it possible to simultaneously record cardiovascular and bronchial parameters, indicate that various components are involved in the responses produced by PAF. It is suggested that different mechanisms depending on the relative contribution of these components may account for the PAF-induced effects at the pulmonary vascular and airway levels.

Evidence for sympathetic neurotransmission through presynaptic N-type calcium channels in human saphenous vein.

1. The specific type(s) of voltage-sensitive calcium channels (VSCCs) involved in sympathetic neurotransmission have not yet been characterized in human vascular tissues. We therefore examined the functional role of the N- and L-type VSCCs in human saphenous veins. 2. Contractile response curves for transmural nerve stimulation (TNS) and for exogenously administered noradrenaline (NA) were obtained in superfused saphenous vein rings. The contractions induced by TNS, but not by NA, were inhibited by 1 microM tetrodotoxin and by 10 microM guanethidine. Both responses were substantially reduced by 1 microM phentolamine, indicating that the contractions evoked by TNS were mediated by endogenous NA released from noradrenergic nerves. 3. In the presence of 2 microM omega-conotoxin GVIA (omega Conus Geographus toxin, fraction VI A; omega-CgTx), a polypeptide with specific inhibitory activity on N- and L-type calcium channels, the neurally evoked contractions were almost completely abolished. In contrast, the responses induced by exogenous NA were not affected by the neurotoxin, thus providing evidence of the exclusive presynaptic action of omega-CgTx. 4. In the presence of the calcium antagonist verapamil (10 microM), which selectively blocks L-type VSCCs, the contractions induced by both TNS and NA were diminished to the same extent, suggesting that the organic calcium blocker is active only at the postjunctional level. 5. It is concluded that N-type calcium channels are the main pathway of calcium entry controlling the functional responses induced by activating sympathetic nerves; the role of L-type channels appears to be limited to the postjunctional level, modulating smooth muscle contractions.

Nitric oxide (NO) modulation of PAF-induced cardiopulmonary action: interaction between NO synthase and cyclo-oxygenase-2 pathways.

1. To further investigate into the mechanisms of PAF-induced cardiopulmonary actions, we examined the effects of the nitric oxide synthase (NOS) inhibitor L-N(omega)-nitro-L-arginine (L-NNA), of the specific cyclooxygenase-2 (COX-2) inhibitor NS 398, and of the combined presence of both COX and NOS inhibitors on the PAF responses in the heart lung preparation of guinea-pig (HLP). 2. In HLPs perfused with homologous blood, dose-response curves for the haemodynamic and bronchial effects of PAF (1 - 32 ng) were carried out in the absence or presence of L-NNA (200 microM). L-NNA caused an increase in the resting pulmonary arterial pressure (PAP) without affecting the other basal values, and strongly potentiated the bronchoconstriction and pulmonary hypertension elicited by PAF. An enhancement of the PAF-induced actions on right atrial pressure (RAP) and cardiac output (CO) was also observed. All the effects of L-NNA were antagonized by L-arginine (2 mM). 3. The presence of L-NNA in the perfusing blood of HLPs failed to affect the pulmonary hypertensive and bronchoconstrictor responses induced by the thromboxane A(2) mimetic U46619 (0.05 - 1.6 microg), 5-hydroxytryptamine (0.1 - 1.6 microg), and histamine (0.1 - 1.6 microg), thus suggesting that these PAF secondary mediators are not responsible for the hyper-responsiveness to PAF induced by L-NNA. 4. Blocking COX-2 pathway with NS 398 (15 - 30 microM) did not alter the cardiopulmonary resting variables. However, a reduction of the PAF-mediated pulmonary hypertension, but not of bronchoconstriction, was observed. When L-NNA was added to the perfusing medium of HLPs pre-treated with NS 398 or with indomethacin (15 microM), the basal PAP values were enhanced. However, in the combined presence of COX and NOS inhibitors, only a slight increase in the hypertensive responses to the highest doses of PAF was observed, whereas the PAF mediated actions at bronchial and cardiac level were unaffected. 5. This study indicates that (i) the cardiopulmonary actions induced by PAF are specifically modulated by endogenous NO through the NOS pathway, and (ii) COX-2 isoform is involved in the pulmonary hypertensive, but not bronchoconstrictor, effects of PAF. Furthermore, an interaction between PAF stimulated COX, particularly COX-2, and NOS pathways appears to take a functional role at both bronchial and cardiovascular level.

Neuropeptide Y-induced potentiation of noradrenergic vasoconstriction in the human saphenous vein: involvement of endothelium generated thromboxane.

1. We investigated the potentiating effect of low concentrations of neuropeptide Y (NPY) on the vasoconstriction induced by transmural nerve stimulation (TNS) and noradrenaline (NA) in human saphenous veins. The effects of (i) endothelium removal; (ii) the addition of the NO pathway precursor L-arginine; (iii) the ET(A)/ET(B) endothelin receptor antagonist Ro 47-0203; (iv) the cyclo-oxygenase inhibitor, indomethacin; (v) the selective thromboxane A2 (TxA2) receptor antagonists Bay u3405 and ifetroban, and (vi) the TxA2 synthase inhibitor, UK 38485, were studied in order to gain information about the mechanisms of NPY-induced potentiation. 2. Contractile response curves for TNS (0.5-8 Hz) and for exogenously administered NA (0.1-3 microM) were obtained in superfused saphenous vein rings. The contractions induced by both TNS and NA at all tested frequencies and concentrations, respectively, were significantly potentiated by 50 nM NPY in endothelium intact veins. Conversely, in endothelium-denuded vessel rings the contractile-response curves to TNS and NA overlapped both in the absence and presence of NPY, thus suggesting that a release of vasoactive substances from endothelial cells could account for the noradrenergic NPY-induced potentiation. 3. In vessels with intact endothelium, the potentiating action of NPY on TNS and NA was unaffected by the presence of high concentrations of the NO precursor L-arginine (3-10 mM) or the non-selective ET(A)/ET(B) endothelin receptor antagonist, Ro 47-0203 (10 microM). These data indicate that the NPY-induced effect does not involve either the endothelium-derived vasodilator nitric oxide or the vasoconstrictor endothelin. Conversely, in the presence of the cyclo-oxygenase inhibitor, indomethacin (30 microM), NPY failed to potentiate the vasoconstrictions produced by either nerve stimulation or by exogenous NA, thus providing evidence that arachidonic acid metabolites through the cyclo-oxygenase pathway are mainly responsible for the potentiation evoked by NPY. 4. When the TxA2 receptor antagonists, Bay u 3405 (1 microM) and ifetroban (1 microM) were added to the superfusing medium, NPY did not alter either the frequency- or the concentration-response curves for either TNS or NA. Accordingly, both TNS- and NA-induced contractions were not potentiated by NPY in the presence of the TxA2 synthase inhibitor, UK 38485 (10 microM). This clearly demonstrates the pivotal role of TxA2 in NPY-induced potentiation. 5. In superfused vein rings with endothelium, a subthreshold concentration (0.2 nM) of the TxA2 mimetic U 46619 potentiated both TNS- and NA-induced vasoconstrictions. This potentiation was higher at low stimulation frequencies and low NA concentrations, and resembled that produced by NPY. 6. Our results indicate that in the human saphenous vein NPY potentiates the contractions produced by sympathetic nerve stimulation acting at the postjunctional level, primarily on endothelial cells. In particular, the NPY-induced release of a cyclo-oxygenase metabolite, namely TxA2, may have a synergistic effect on the vasoconstriction induced by the noradrenergic mediator. Thus, such a mechanism may play a key role in the maintenance of the sympathetic tone of large human capacitance vessels.

Thromboxane generation and pulmonary reactivity to arachidonic acid in heart-lung preparation of guinea-pig: modulation by PCO2.

A dose-related increase of pulmonary vasoconstrictive and bronchoconstrictive effects, as well as of the amounts in the perfusing fluid of TXB2, the stable metabolite of TXA2, was obtained through administration of arachidonic acid (AA) in normocapnic and deeply hypocapnic guinea-pig heart-lung preparations (HLPs) perfused with homologous red blood cells suspended in a modified Tyrode solution. Pulmonary hypertensive effects and the amounts of TXB2 detected in the perfusing fluid were reduced in hypocapnic preparations as compared with the normocapnic ones, while the bronchoconstrictive responses to AA were not affected by CO2 tension. It is concluded that: a) biosynthesis of TXA2 is reduced in hypocapnic group if compared with that observed in normocapnic one, b) the quantitative change of AA metabolism is responsible for hypocapnia reduction of pulmonary vasoconstrictive effects of AA, c) stability of bronchoconstriction due to AA infusions in normocapnic and hypocapnic HLPs might indicate an up regulation for TXA2 bronchial smooth muscle receptors by hypocapnia.

Effects of cardioplegic solutions and their components on human saphenous vein contractility.

Cardioplegic solution administration into the vein graft is an established method to ensure cardioplegic distribution beyond coronary artery stenoses. The ultrastructural demonstration of severe endothelial damage after cardioplegic exposure suggests that intravenous cardioplegic administration can contribute to early and late graft thrombosis. The direct effect on human saphenous vein contractility of three cardioplegic solutions and their components was compared. A solution with 30 mmol/L K+ and 82 mmol/L Na+ produced intense venoconstriction. Lowering the potassium level to 10 mmol/L and increasing the sodium level to 92 mmol/L reduced its vasoconstricting action. A third solution with 16 mmol/L K+, 16 mmol/L Mg2+, and lidocaine caused venodilatation. Analysis of the single component effects showed that high potassium level, low sodium level, and the addition of lidocaine produced concentration-dependent vasoconstriction. High magnesium concentration resulted in vasodilatation. The present data suggest that cardioplegic solution composition may cause marked vasomotor effects on saphenous vein and thus influence its endothelial integrity. In the search for an "ideal solution" to the cardioplegic controversy, a venoconstrictor infusate should be avoided to improve patency rates of coronary artery bypass grafts.

Nitric oxide-dependent and -independent modulation of sympathetic vasoconstriction in the human saphenous vein.

The possible modulation by the endothelium of the contractile responses to sympathetic nerve stimulation was examined in isolated superfused human saphenous vein. Contractile response curves for transmural nerve stimulation and noradrenaline were higher in endothelium-denuded than in intact human saphenous vein rings. In vessels with endothelium, transmural nerve stimulation- and noradrenaline-induced contractions were unaffected by the cyclooxygenase inhibitor, indomethacin (10 microM), but were potentiated by the nitric oxide (NO) synthase inhibitor, L-N omega-nitro-L-arginine (L-NNA, 3 microM) even when combined with D-arginine (0.3 mM), but not with L-arginine (0.3 mM). As in the case of noradrenaline, contractile responses to 5-HT, but not to KCI, were enhanced by endothelium removal, L-NNA or L-NNA plus D-arginine, but were unaffected by L-NNA plus L-arginine. The guanylyl cyclase inhibitor, methylene blue (10 microM), potentiated both transmural nerve stimulation- and noradrenaline-induced contractions in endothelium intact rings, whereas it enhanced, although to a lesser degree, only the neurally evoked contractions in endothelium-denuded human saphenous vein. In the vessels without endothelium L-NNA failed to affect the vasoconstriction induced by both transmural nerve stimulation and noradrenaline. Our results suggest that at least two inhibitory factors are involved in modulating the sympathetic vasoconstriction in the human saphenous vein: (1) at a postjunctional level, NO, the release of which from endothelial cells is probably stimulated by the activation of specific receptors, and (2) at a prejunctional level, an unidentified vasodilator agent, which is unmasked by the removal of the endothelium layer and which is probably co-released along with noradrenaline, and which acts through the guanylyl cyclase pathway.

Vascular reactivity in perinatally undernourished rats.

Adult rats submitted to perinatal protein deprivation (from day 14 of fetal life till 50 days of age) followed by a longer phase of nutritional recovery on balanced laboratory chow, showed a significant decrease of the pressor response elicited by noradrenaline and adrenaline, an effect that persisted after ganglionic blockade by hexamethonium. However, the effects of serotonin, acetylcholine, angiotensin II and vasopressin on blood pressure did not differ from those in the controls. Cumulative dose-response curves to noradrenaline and methoxamine on the circular contraction of isolated iliac arteries showed a significant shift to the right, together with a reduction in the maximal contraction. No significant difference in the maximal contraction elicited by Ba2+ was observed in experimental preparations as compared with controls. These results suggest the development of a specific subsensitivity to sympathetic drugs in the vascular bed as a consequence on undernutrition during perinatal life.

Immune imbalance in the synovial fluid of rheumatoid arthritis patients: effects of intra-articular injection of thymopentin.

T cell subsets in the synovial fluid (SF) and peripheral blood (PB) of RA patients and controls suffering from different forms of chronic synovitis have been investigated. The immunological evaluation showed a reduction of CD4 subsets in RA-SF compared to RA-PB (p less than 0.001), and an almost complete absence of the suppressor-inducer/naive T cells in RA-SF compared to RA-PB and SF from patients with other forms of chronic synovitis. The CD8 subpopulation showed an increased proportion of cytotoxic cells only in RA-SF. On the basis of these results, an intra-articular immunomodulating treatment with thymopentin has been performed: its effects were characterized by an increase of CD8+CD11b+ T cells in the CD8 subset parallel to the enhancement of the suppressor-inducer/naive T cells in the CD4 subset with a statistically significant correlation. The enhanced levels of soluble CD8 decreased after treatment in RA-SF, whereas the soluble IL-2R levels were not significantly modified. Clinical evaluation showed a significative amelioration in all considered parameters.

[Levodopa treatment of a case of torsion spasm with athetosis]. / Trattamento con Levodopa di un caso di spasmo di torsione con atetosi.

The result about Levodopa treatment in torsion dystonia and athetosis are quite contradictory. We report an interesting case, significant for the results that we obtained in a long treatment period. A girl was suffering from age of 8 years of torsion dystonia associated with athetosis. We made our first clinical examination when 12 years old: she was not able to stand-up and to walking, neither was she able to be sitting in a chair without arms. In two months of treatment with Levodopa 3.000 mg. by day, the symptoms completely disappeared. During the first two years of treatment, at every effort to decrease the therapy we observed an important increase of symptoms. Successively it was possible to decrease the therapy and now, after 8 years of treatment, with a minimal dose, the girl doesn't show any symptoms, so that she can manage a normal relative life. Probably these good results depend on the fact that was a sporadic recessive form of torsion dystonia case.

[Beta interferon therapy of HPV infections of the female genital tract]. / Trattamento con beta-interferone nelle infezioni da HPV dell'apparato genitale femminile.

The aim of the study was to evaluate the incidence of cervical and vaginal lesions due to Papilloma virus before and after beta-interferon therapy. Clinical symptoms and the therapeutic approach are described, whereas drug efficacy was assessed on a long-term basis. The study of 19 cases, brought to the Author's attention over an eight-year period (1984-91) confirms previously published reports: the use of interferon shows a good level of tolerability without complications and undeniable efficacy following surgical treatment.

Association among genetic predisposition, gut microbiota, and host immune response in the etiopathogenesis of inflammatory bowel disease.

Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a chronic disorder that affects thousands of people around the world. These diseases are characterized by exacerbated uncontrolled intestinal inflammation that leads to poor quality of life in affected patients. Although the exact cause of IBD still remains unknown, compelling evidence suggests that the interplay among immune deregulation, environmental factors, and genetic polymorphisms contributes to the multifactorial nature of the disease. Therefore, in this review we present classical and novel findings regarding IBD etiopathogenesis. Considering the genetic causes of the diseases, alterations in about 100 genes or allelic variants, most of them in components of the immune system, have been related to IBD susceptibility. Dysbiosis of the intestinal microbiota also plays a role in the initiation or perpetuation of gut inflammation, which develops under altered or impaired immune responses. In this context, unbalanced innate and especially adaptive immunity has been considered one of the major contributing factors to IBD development, with the involvement of the Th1, Th2, and Th17 effector population in addition to impaired regulatory responses in CD or UC. Finally, an understanding of the interplay among pathogenic triggers of IBD will improve knowledge about the immunological mechanisms of gut inflammation, thus providing novel tools for IBD control.

Classical and recent advances in the treatment of inflammatory bowel diseases

Crohn's disease (CD) and ulcerative colitis (UC) are intestinal disorders that comprise the inflammatory bowel diseases (IBD). These disorders have a significant effect on the quality of life of affected patients and the increasing number of IBD cases worldwide is a growing concern. Because of the overall burden of IBD and its multifactorial etiology, efforts have been made to improve the medical management of these inflammatory conditions. The classical therapeutic strategies aim to control the exacerbated host immune response with aminosalicylates, antibiotics, corticosteroids, thiopurines, methotrexate and anti-tumor necrosis factor (TNF) biological agents. Although successful in the treatment of several CD or UC conditions, these drugs have limited effectiveness, and variable responses may culminate in unpredictable outcomes. The ideal therapy should reduce inflammation without inducing immunosuppression, and remains a challenge to health care personnel. Recently, a number of additional approaches to IBD therapy, such as new target molecules for biological agents and cellular therapy, have shown promising results. A deeper understanding of IBD pathogenesis and the availability of novel therapies are needed to improve therapeutic success. This review describes the overall key features of therapies currently employed in clinical practice as well as novel and future alternative IBD treatment methods.

Laparoscopic repair of congenital pleuroperitoneal hernia using a polypropylene mesh in a dog / Correção laparoscópica de hérnia pleuroperitoneal utilizando malha de polipropileno em cão

Pleuroperitoneal hernias are the most uncommon type of diaphragmatic hernias in dogs and cats. The treatment of choice is surgery and may involve the use of prosthetic implant through celiotomy. In the current report, laparoscopic repair of a congenital pleuroperitoneal hernia using polypropylene mesh in a dog is described. The surgery was feasible. Appropriate reduction of the hernia was carried out and no complications were noted.

Hérnias pleuroperitoneais são o tipo mais incomum de hérnias diafragmáticas em cães e gatos. O tratamento de escolha é cirúrgico e pode envolver o uso de implantes protéticos na abordagem via laparotomia. No presente relato, é descrito o reparo de uma hérnia pleuroperitoneal congênita através de laparoscopia com utilização de malha de polipropileno. A cirurgia foi viável. Houve redução apropriada da hérnia sem observação de complicações.