The vagal nerve as a link between the nervous and immune system in the instance of polymicrobial sepsis

Background The role of the vagal nerve in the autonomic nervous system is widely well known. Recently, an additional function was revealed serving as a connector between the nervous and immune system. This connection is called the “cholinergic inflammatory pathway.” Through stimulation of the acetylcholine receptors located upon the macrophages, the “unspecific” immune system can be directly influenced. Methods The vagal nerve was completely transected directly posterior to its passage through the diaphragm. The effect of complete vagotomy was analyzed using a murine model of polymicrobial peritonitis (colon ascendens stent peritonitis, CASP). Survival and clinical course of vagotomized or sham-operated mice were analyzed in the CASP model. Results After CASP surgery, vagotomy led to a significantly increased mortality (64.7%) in comparison to sham-vagotomized animals (34%). No difference in the bacterial load of various tissues (lung, liver, spleen, blood, lavage fluid, and kidney) from septic animals with or without vagotomy was observed. Vagotomized animals reveal elevated serum cytokine levels (TNF, IL-6, IL-10, and MCP-1) 20 h after the induction of polymicrobial peritonitis. Conclusion The vagal nerve is therefore an important modulator of the immune system. W. Kessler and T. Traeger contributed equally to this work Best of Forum Papers presented at the Annual Meeting of the German Society of Surgery, 2–5 May 2006, Berlin, Germany     

Usefulness of PCR Strategies For Early Diagnosis of Chagas'' Disease Reactivation and Treatment Follow-Up in Heart Transplantation

Heart transplantation (HTx) is a useful therapy for end‐stage Chaga? cardiomyopathy; however, Chagas reactivation remains a mayor complication. Parasitological methods offer poor diagnostic sensitivity, and use of more sensitive tools such as the Polymerase chain reaction (PCR) is usually necessary. In the present study, reactivation incidence and PCR usefulness for early reactivation diagnosis, as well as for treatment response evaluation during follow‐up, were analyzed using Strout parasite detection test, in 10 of 222 consecutive HTx patients suffering Chagas cardiomyopathy. PCR strategies targeted to minicircle sequences (kDNA, detection limit 1 parasite/ 10 mL blood) and miniexon genes (SL‐DNA, 200 parasite/10 mL) were performed to compare parasite burdens between samples. No patients received prophylactic antiprotozoal therapy (benznidazole). Five patients (50%) exhibited clinical reactivation within a mean period of 71.6 days; positive Strout results were observed in most cases presenting clinical manifestations. kDNA‐PCR was positive 38–85 days before reactivation, whereas SLDNA‐PCR became positive only 7–21 days later, revealing post‐HTx parasitic load enhancement present prior to clinical reactivation development. Reactivations were successfully treated with benznidazole and generated negative PCR results. Results observed in this study indicate the value of PCR testing for an early diagnosis of Chagas reactivation as well as for monitoring treatment efficacy.     

Differential Stripping: Determination of the Amount of Topically Applied Substances Penetrated into the Hair Follicles

The determination of penetration pathways of topically applied substances into the skin is the subject of several investigations. Recently, follicular penetration has become a major focus of interest. To date, a direct, non-invasive quantification of the amount of topically applied substance penetrated into the follicles had not been possible. The development of such a method was the aim of this study. Therefore, the advantages of both stripping techniques, tape stripping and cyanoacrylate skin surface biopsy, were combined and evaluated. Tape stripping was used to remove the part of the stratum corneum that contained the topically applied dye. Subsequently, the follicular contents were ripped off by cyanoacrylate skin surface biopsy. The combined method termed "differential stripping" was evaluated in vitro and in vivo , and the amount of topically applied fluorescent dye penetrated into the hair follicles was quantified after different penetration times. After 30 min, 5% of the recovered concentration of sodium fluorescein was found in the follicular infundibula, where it was still detectable after 48 h. Altogether, the results of this investigation revealed that differential stripping is a new method that can be used to study the penetration of topically applied substances into the follicular infundibula non-invasively and selectively.     

Endovaskuläre Brachytherapie als neue Therapieoption zur Prophylaxe der Rezidivstenose nach peripherer Katheterintervention

The therapeutic concept of irradiation of the vessel wall for prevention of restenosis after endovascular procedures is based on increasing knowledge about the pathophysiology of the process leading to restenosis. There is until now only a limited number of studies concerning the use of brachytherapy (BT) in the peripheral circulation, which is in contrast to the already large experience in the coronary circulation. In the peripheral trials the radiation dose was administered by a remote afterloader using a gamma source. According to the available data, vascular BT is a promising technology with the potential to reduce the restenosis rate. The Vienna-2-Trial was the first randomised study to demonstrate the efficacy of endovascular BT for prophylaxis of restenosis after femoropopliteal percutaneous transluminal angioplasty. However, we have to await further supportive data from ongoing clinical trials before definitive recommendations can be given. Currently, endovascular BT seems already justified in patients with recurrent interventions or after long-segment femoropopliteal angioplasty because of the high risk of restenosis in these patients. The next years will demonstrate the ultimate role of endovascular BT in comparison to the rapidly evolving field of drug-eluting stents.     

Demonstration of endothelial adhesion of sickle cells in vivo: a distinct role for deformable sickle cell discocytes.

Different morphologic and density classes of sickle cells (SS) may play distinct roles in the generation of vasoocclusion, explaining the complexity of this phenomena. The densest SS red blood cells (RBCs) (SS4) can induce vasoocculsion in ex vivo microcirculatory preparations as well as in an intact animal model. Previous studies of the interaction of SS deformable discocytes with endothelial monolayers or the rat ex vivo mesocecum preparation have shown adhesion that is desmopressin (dDAVP)-stimulated, von Willebrand factor (vWF)-mediated, and limited to the small venules. However, in vivo adhesion of SS RBCs to the endothelium has neither been demonstrated nor characterized; and, in particular, the relation of adhesion to vasoocclusion is unknown. Using an intact animal model that involves injecting saline-washed, density-defined SS RBCs into the femoral artery of a rat, we find that: (1) Quantitative studies of RBCs retained in the rat thigh using 99mTc-labeled RBCs and gamma camera imaging showed that dDAVP induces a threefold increase in retention of normal (AA) cells and deformable SS discocytes (SS2). (2) electron microscopy and Microfil injection show that the retention of SS2 cells is due to adhesion to the vascular endothelium with no evidence of obstruction. (3) H-1 magnetic resonance imaging showed that retention of SS4 cells induced a dose-dependent increase in tissue edema (presumable secondary to tissue hypoxia), while retention of AA or SS2 cells produced no change. We conclude that endothelial adhesion of deformable SS discocytes can be demonstrated in an in vivo animal model, that this adhesion is enhanced by dDAVP (presumably related to, but not necessarily limited to the release of vWF), and that this phenomenon per se does not lead to vasoocclusion. Nevertheless, adhesion of deformable SS discocytes may have consequences. We hypothesize that adhesion of SS discocytes could narrow the lumen of postcapillary venules and facilitate secondary trapping of SS4 cells and lead to subsequent vasoocclusion.     

Neue Entwicklungen in der systemischen Psoriasistherapie

The current standard systemic therapeutic modalities for psoriasis have many potential side effects. Progress made in the understanding of the pathophysiology of psoriasis as a T‐cell‐mediated dermatosis provide options for new more precise therapeutic approaches. These immunological therapeutic strategies involve the inhibition/depletion of activated T‐lymphocytes, the inhibition of antigen presentation and thus the regulation of T‐cell activation, the inhibition of adhesion of inflammatory cells, the inhibition of effects of proinflammatory mediators and the administration of antiinflammatory cytokines. This article summarizes these new systemic therapeutic approaches. Clinical results in the early studies have been mixed. In the next years further results of phase II‐ and phase III‐studies may be expected, which should allow better assessment of the potential of those particular approaches. Some of these approaches could lead to the approval of new drugs to treat psoriasis and to enhance or replace already existing therapeutic options. Furthermore results of therapeutic experiments should contribute to a better understanding of the disease. As we learn which mechanisms are more or less important for the disease, we will be better able to plan intervention strategies.     

Abdominalchirurgisch relevante Aspekte des Suizidversuchs

In this retrospective study of 24 patients who were treated at our clinic during the last 22 years after having attempted suicide, we evaluated aspects concerning abdominal-and transplantation surgery. There was a predominance of “hard” (70%) versus “soft” (30%) methods for suicide attempt. Intra-abdominal injuries resulting from attempted suicide by stabbing or shooting should lead to laparotomy— the prognosis is then good. Surgical treatment after intoxication, especially caustic ingestion, depends on endoscopic and clinical findings. The highly increased rates of suicide significantly by kidney transplantation. The risk of suicide after transplantation is further diminished with improved immunosuppressive treatment. Only in a few cases there is an indication for liver transplantation— in some cases of fulminant hepatic failure caused by self-administered paracetomol overdose. Auxiliary liver transplantation may then be considered.     

Systemic endotoxin and gastric mucosal pH are the best parameters to predict lethal outcome in a porcine model of abdominal sepsis according to multivariate analysis.

This study was devised to identify sepsis-relevant parameters that early and reliably predict a lethal outcome in intra-abdominal sepsis. In 18 Duroc pigs, peritonitis was induced through standardized gastrotomy. Twelve hours later the defect was oversewn and the abdominal cavity lavaged thoroughly. Sepsis relevant parameters were measured before initiating therapy, and 30 min later animals were extubated and observed for a period of 6 days under adequate analgesia with free access to water and food. All parameters were correlated with survival postoperatively. In the treatment group, 7 out of 18 pigs (39%) died within the observation period. Endotoxin level at 30 min after initiation of therapy [17.9 EU/mL (+/- 12.1) vs. 110.9 EU/mL (+/- 21); p <.001] and Delta pHi [0.015 (+/- 0.011) vs. -0.039 (+/- 0.013); p =.016] were identified as the two parameters with highest predictive power regarding mortality in a multivariate analysis. In conclusion measurement of endotoxin and gastric tonometry should gain wider clinical application in septic patients.     

Lambert-Eaton myasthenic syndrome IgG depletes presynaptic membrane active zone particles by antigenic modulation

The Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease that can be transmitted from human to mouse with immunoglobulin G (IgG). Electrophysiological studies indicate that LEMS IgG acts on presynaptic voltage-sensitive calcium channels, probably reducing their number, and freeze-fracture electron microscopy demonstrates that LEMS IgG has an effect on the presynaptic active zone particles, which represent putative voltage-sensitive calcium channels. The active zone particles, normally arranged in double parallel rows, move closer together, form clusters, and are reduced in number. The morphological data suggest modulation of the active zone particles crosslinked by LEMS IgG. If this were the case, then only divalent LEMS IgG and F(ab')2 should alter the deployment of active zone particles and monovalent Fab should be without effect. To test this hypothesis, mouse diaphragms were exposed to control and LEMS IgG and IgG fragments in organ culture for 24 hours and then studied by quantitative freeze-fracture electron microscopy. Divalent LEMS IgG and F(ab')2 aggregated and depleted the active zone particles, whereas monovalent Fab had no effect. The findings reconfirm that the active zone particles are targets of LEMS IgG and are direct evidence for modulation of the particles by LEMS IgG. The findings are in harmony with parallel electrophysiological studies of the effects of LEMS IgG fragments on transmitter release in the same diaphragm muscles (Lang et al, J Physiol 1987;390:173P).