[Digitalization in rheumatological practice]. / Digitalisierung in der Rheumapraxis.

Digitalization in medicine is of major interest since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. This article tries to present the induced changes and technical solutions with respect to the different parts in the patient journey. Symptom checkers, new health applications, digital appointment management etc. are described. Apart from the technical and digital possibilities, the changes in the quality of communication additionally have to be mentioned. There is an urgent need for further technical standardization including the interfaces. In many cases further studies must confirm the equivalence of digital applications in comparison to analogue techniques.

[Endocrinology and interdisciplinary consultation in internal medicine : Illustrated using the example of polyglandular autoimmune syndrome]. / Endokrinologie als Schnittstelle in der interdisziplinären Inneren Medizin : Veranschaulichung anhand des polyglandulären Autoimmunsyndroms.

Polyglandular autoimmune syndromes encompass several endocrine and nonendocrine autoimmune disorders with variable onset and phenotype. Rheumatoid and gastroenterological symptoms in patients with autoimmune polyglandular syndromes are suggestive of additional rheumatoid gastrointestinal and hepatological autoimmune diseases. Autoimmune gastritis, celiac disease, autoimmune hepatitis, rheumatoid arthritis, Sjögren syndrome, and systemic Lupus erythematodus are of particular clinical relevance. In addition, unspecific rheumatoid and gastrointestinal attendant symptoms of the existing autoimmune endocrinopathy must be considered. Furthermore, certain disorders of polyglandular autoimmune syndromes, e. g., type 1 diabetes are frequently associated with particular gastrointestinal diseases such as small bowel bacterial overgrowth. An optimal patient-centered care of subjects with autoimmune diseases requires a comprehensive differential diagnostic work up and emphasizes the importance of an interdisciplinary cooperation.

[Range of variation of pancreaticojejunostomy in pancreatic head resection]. / Variationsbreite der Pankreatojejunostomie bei Pankreaskopfresektion.

Leakage of pancreaticojejunostomy basically determines the morbidity and mortality of pancreatic head resection. Aggressive pancreatic juice affects the integrity of the anastomosis and the occurrence of local pancreatitis is increased due to manipulation of the pancreas during creation of the anastomosis. A multitude of anastomotic techniques have been developed aimed at minimizing the leakage rate of up to 20%. Ideal would be a simple technique that can be carried out independently of the softness of the pancreas and the diameter of the pancreatic duct. We present three anastomotic techniques: the classical duct-to-mucosa pancreaticojejunostomy (Cattell-Warren anastomosis), the invagination pancreaticojejunostomy and the Blumgart anastomosis. Based on the available literature, the advantages and disadvantages of each technique are explained. The Blumgart anastomosis and the invagination pancreaticojejunostomy seem to be superior to the Cattell-Warren anastomosis; however, the available data cannot be directly compared. Currently, a prospective randomized study is being conducted to evaluate the importance of the Blumgart anastomosis.

[Pylorus-preserving pancreatic head resection. Video article]. / Pyloruserhaltende Pankreaskopfresektion. Videobeitrag.

The pylorus preserving pancreatoduodenectomy (PPPD) is a surgical procedure for the treatment of pancreatic head cancer, distal bile duct tumors and malignancies of the duodenum. This surgical technique can also be applied to treat chronic pancreatitis. The perioperative mortality rate ranges between 3% and 5%. The procedure is performed in a standardized way. It begins with the exploration phase to clarify resectability of the tumor. Subsequently it is divided into a structured resection and reconstruction phase. Malignant tumors require a systematic lymphadenectomy of the hepatoduodenal ligament. Since the complication rate is not negligible, complication management plays an important role. Most frequently, delayed gastric emptying and pancreatic fistulas occur. We present an accompanying video of this operation online, where the PPPD procedure is performed to treat duodenal polyps in familial adenomatous polyposis after failure of endoscopic ablation.

[Papillary tumors - therapeutic concepts]. / Papillentumoren - therapeutische Konzepte.

Papillary tumors originate from the various structures of the ampulla of Vater; therefore, these rare tumors represent a heterogeneous group of tumor entities. Intestinal differentiated adenomas are the most common benign lesions, whereas intestinal differentiated papillary carcinomas are the most common malignant tumors. Carcinomas with pancreaticobiliary differentiation have a poorer prognosis. Mesenchymal and neuroendocrine tumors are among the least frequent papillary tumors. Diagnosis is performed by side-view upper endoscopy and biopsy. In cases of suspected malignancy a complete staging with computed tomography (CT) and endoscopic ultrasound scanning is indicated to determine local tumor spread.Adenomas are removed by endoscopic snare papillectomy whereas the therapy of choice for papillary carcinomas is pancreatic head resection with systematic lymphadenectomy. Patients with papillary carcinomas are most likely to benefit from adjuvant therapy, which should be determined in an interdisciplinary consensus conference considering the histological differentiation of the tumor.

[Arterial and portal venous complications after HPB surgical procedures: Interdisciplinary management]. / Arterielle und portalvenöse Gefäßkomplikationen nach HBP-Eingriffen : Interdisziplinäres Management.

The surgical treatment of hepatopancreatobiliary (HPB) diseases requires complex operative procedures. Within the last decades the morbidity (36-50 %) and mortality (<5 %) of these procedures could be reduced; nonetheless, postoperative complications still occur in 41.2 % of cases. Compared with hepatobiliary procedures, pancreatic surgery shows an increased rate of complications. Postoperative bleeding has a major effect on the outcome and the incidence is 6.7 % after pancreatic surgery and 3.2 % after hepatobiliary surgery. The major causes of early postoperative hemorrhage are related to technical difficulties in surgery whereas late onset postoperative hemorrhage is linked to anastomosis insufficiency, formation of fistulae or abscesses due to vascular arrosion or formation of pseudoaneurysms. In many cases, delayed hemorrhage is preceded by a self-limiting sentinel bleeding. The treatment is dependent on the point in time, location and severity of the hemorrhage. The majority of early postoperative hemorrhages require surgical treatment. Late onset hemorrhage in hemodynamically stable patients is preferably treated by radiological interventions. After interventional hemostatic therapy 8.2 % of patients require secondary procedures. In the case of hemodynamic instability or development of sepsis, a relaparotomy is necessary. The treatment concept includes surgical or interventional remediation of the underlying cause of the hemorrhage. Other causes of postoperative morbidity and mortality are arterial and portal venous stenosis and thrombosis. Following liver resection, thrombosis of the portal vein occurs in 8.5-9.1 % and in 11.6 % following pancreatic resection with vascular involvement. Interventional surgical procedures or conservative treatment are suitable therapeutic options depending on the time of diagnosis and clinical symptoms. The risk of morbidity and mortality after HPB surgery can be reduced only in close interdisciplinary cooperation, which is particularly true for vascular complications.

MSC-based therapies in solid organ transplantation.

Immunomodulatory cell therapy as a complement to standard pharmacotherapy represents a novel approach to solid organ allograft acceptance. This methodology may allow for a reduced dose of immunosuppressive drug to be administered and thus attenuate the severe side effects associated with long-term immunosuppression such as drug-related impairment of renal function, increased risk from opportunistic infections and malignancies. Mesenchymal stem cells (MSCs) have been shown to possess both immune modulatory and regenerative properties in vitro and in preclinical models. Encouraging results have been reported from studies examining the safety and efficacy of MSCs as a treatment for acute graft-versus-host disease. MSCs represent a promising candidate cell therapy to supplement immunosuppression in recipients of solid organs, and initial reports on the clinical use of MSCs in kidney transplantation have been recently published (Tan et al. in J Am Med Assoc 307:1169-1177, 2012; Reinders et al. in Stem Cells Transl Med 2:107-111, 2013; Perico et al. in Transpl Int 26:867-878, 2013; Perico et al. in Clin J Am Soc Nephrol 6:412-422, 2011). An area of even greater interest might be the application of MSCs in clinical liver transplantation as graft survival is closely associated with overall patient survival. Here, we present preclinical findings and discuss their possible impact on clinical liver transplantation. Then we discuss clinical studies designed to investigate how MSCs may be distributed and act in solid organ transplantation.

Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion.

Mesenchymal stem cells (MSC) are under investigation as a therapy for a variety of disorders. Although animal models show long term regenerative and immunomodulatory effects of MSC, the fate of MSC after infusion remains to be elucidated. In the present study the localization and viability of MSC was examined by isolation and re-culture of intravenously infused MSC. C57BL/6 MSC (500,000) constitutively expressing DsRed-fluorescent protein and radioactively labeled with Cr-51 were infused via the tail vein in wild-type C57BL/6 mice. After 5 min, 1, 24, or 72 h, mice were sacrificed and blood, lungs, liver, spleen, kidneys, and bone marrow removed. One hour after MSC infusion the majority of Cr-51 was found in the lungs, whereas after 24 h Cr-51 was mainly found in the liver. Tissue cultures demonstrated that viable donor MSC were present in the lungs up to 24 h after infusion, after which they disappeared. No viable MSC were found in the other organs examined at any time. The induction of ischemia-reperfusion injury in the liver did not trigger the migration of viable MSC to the liver. These results demonstrate that MSC are short-lived after i.v. infusion and that viable MSC do not pass the lungs. Cell debris may be transported to the liver. Long term immunomodulatory and regenerative effects of infused MSC must therefore be mediated via other cell types.

Mesenchymal stem cells together with mycophenolate mofetil inhibit antigen presenting cell and T cell infiltration into allogeneic heart grafts.

Donor-derived mesenchymal stem cells (MSC) can induce long-term acceptance in a rat heart transplantation model when injected prior to transplantation in combination with mycophenolate mofetil (MMF). In contrast, MSC alone cause accelerated graft rejection. To better understand these conflicting data we studied the effects of MSC and MMF on lymphocyte populations in heart allografts and secondary lymphatic organs. Allogeneic MSC injected prior to transplantation are immunogenic in this model because activated CD4+ and CD8+ cells emerged earlier in secondary lymphatic organs of MSC- and MSC/MMF-treated animals, compared to animals not treated with MSC. Consequently T cells infiltrated the grafts of MSC-only treated animals promptly causing accelerated graft rejection. However, few T cells or antigen-presenting cells (APC) infiltrated the grafts of animals treated with MSC and MMF. Consistent with this finding, intercellular adhesion molecule 1 (ICAM-1) and E-selectin was down-regulated exclusively in MSC/MMF-treated grafts, indicating that MSC together with MMF interfere with endothelial activation. Additionally, the presence of interferon-gamma (IFN-γ) enhanced MSC capabilities to suppress T cell proliferation in vitro. Interestingly, MMF did not influence serum IFN-γ levels in vivo. Together, our data indicate that MSC pre-activate T cells, but co-treatment with MMF eliminates these T cells, decreases intragraft APC and T cell trafficking by inhibiting endothelial activation, and allows IFN-γ stimulation of suppressive MSC.

Antigen-specific recognition is critical for the function of regulatory CD8(+)CD28(-) T cells.

The immunomodulatory properties of CD8 T cells with regulatory phenotype have become evident. It remains unclear whether the immunomodulatory function of CD8(+)CD28(-) T cells requires antigen-specific TCR interaction with major histocompatibility complex class I (MHC I). We have isolated naïve CD8(+)CD28(-) T suppressor cells (Tsup) from H2-Kk Des-TCR mice that express a transgenic, MHC class I-restricted, clonotypic TCR against an allogeneic MHC class I molecule (H2-Kb) plus self-peptide. These cells were compared to B10.BR wild type (w/t) CD8(+)CD28(-) T cells and to naïve CD4(+)CD25(+) regulatory T cells (Treg) of the same strains. Des CD8 effector T cells proliferated more readily when stimulated by H2-Kb splenocytes than w/t controls, whereas Des CD4 T cells showed the same alloresponse as w/t cells. Activation and proliferation of B10.BR CD4 T cells stimulated by H2-Kb APC were suppressed more effectively by Des CD8(+)CD28(-) T cells than by w/t CD8(+)CD28(-) T cells. On the contrary, Des CD4(+)CD25(+) T cells inhibited T cell proliferation less effectively than w/t CD4(+)CD25(+) T cells. In conclusion, we demonstrate that the function of naive Tsup is strongly enhanced by antigen recognition. Therefore we expect that Tsup are possible candidates for antigen-specific immunosuppressive therapy.

Mesenchymal stem cells require a sufficient, ongoing immune response to exert their immunosuppressive function.

Mesenchymal stem cells (MSC) have emerged to be one of the most promising candidates for cellular immunotherapy in solid organ transplantation because the reduction of conventional immunosuppression is highly desirable. However, little is known about the details of MSC-mediated immunomodulation and their clinical relevance. To address conflicting studies about the ability of MSC to suppress or augment T-cell proliferation, we introduce a transplantation-related rat model that allows studying the influence of MSC on alloproliferation. Hearts transplanted in a fully allogeneic transplantation model (LEW to ACI) were rejected earlier when recipients were pretreated with donor MSC, indicating activation of T cells in vivo. In additional co-culture experiments, T cells were differently affected by allogeneic MSC depending on the extent of previous activation: When conditions were rendered proinflammatory by adding high concanavalin A (ConA) concentrations or proinflammatory cytokines (interferon-gamma, interleukin-2, or tumor necrosis factor-alpha), MSC inhibited proliferation. Application of low doses of ConA or anti-inflammatory cytokines like IL-10 abrogated the suppressive effect of MSC. For application of MSC in solid organ transplantation, it will be important to further describe this switch effect of MSC function.

[The techniques of peritonectomy and hyperthermic intraperitoneal chemotherapy]. / Technik der Peritonektomie sowie der hyperthermen intraperitonealen Chemotherapie.

The treatment of peritoneal carcinomatosis represents a challenge in the therapy for gastrointestinal cancer. A multimodal approach with complete surgical cytoreduction and hyperthermic intraperitoneal chemotherapy can improve the prognosis in selected patients. Complete surgical cytoreduction, consisting of parietal and visceral peritonectomy, is a sophisticated procedure, frequently requiring multivisceral resections and should only be performed by experienced visceral surgeons. In addition, hyperthermic intraperitoneal chemotherapy is of some complexity. Furthermore, regarding the learning curve for this procedure, combined treatment should only be performed in specialised centres. Under optimal conditions, the therapy can be carried out with reasonable morbidity and mortality rates. Patients with peritoneal carcinomatosis should be evaluated by an interdisciplinary team concerning this multimodal therapy option and, if applicable, they should be referred to therapy within the framework of clinical studies.

On the dynamics of self-organization in living organisms.

We show that in nonlinear systems dynamical order can be reached through the flows of matter, energy, and information, which can be non uniformly spread over the organism due to self-trapping induced by the correlated coherence domains of interfacial water. Endogenous electromagnetic field is self trapped in these domains and forms the dynamical pathways as wave-guides, along which these flows can occur via soliton mechanisms. Solitons in the pathways can be stimulated either by intrinsic dynamics or by external stimuli and can be visualized in the infrared range as bright or dark solitons. The formation of such pathways is the consequence of coherence-non coherence transitions occurring in the biological cycle of the organism. A rational therapy appears then to be the induction of conditions for soliton existence necessary for maintaining the coherence of the system.

Mesenchymal stem cells can induce long-term acceptance of solid organ allografts in synergy with low-dose mycophenolate.

The induction of tolerance towards allogeneic solid organ grafts is one of the major goals in transplantation medicine. Mesenchymal stem cells (MSC) inhibit the immune response in vitro, and thus are promising candidate cells to promote acceptance of transplanted organs in vivo. Such novel approaches of tolerance induction are needed since, to date, graft acceptance can only be maintained through life-long treatment with unspecific immunosuppressants that are associated with toxic injury, opportunistic infections and malignancies. We demonstrate that donor-derived MSC induce long-term allograft acceptance in a rat heart transplantation model, when concurrently applied with a short course of low-dose mycophenolate. This tolerogenic effect of MSC is at least partially mediated by the expression of indoleamine 2,3-dioxygenase (IDO), demonstrated by the fact that blocking of IDO with 1-methyl tryptophan (1-MT) abrogates graft acceptance. Moreover we hypothesize that MSC interact with dendritic cells (DC) in vivo, because allogeneic MSC are rejected in the long-term but DC acquire a tolerogenic phenotype after applying MSC. In summary, we demonstrate that MSC constitute a promising tool for induction of non-responsiveness in solid organ transplantation that warrants further investigation in clinical trials.

Mesenteric ischemia--outcome after surgical therapy in 83 patients.

BACKGROUND: Intestinal ischemia is the prime vascular emergency for the visceral surgeon. However, the diagnosis of mesenteric ischemia is difficult, the surgical options are often limited and the overall outcome is generally poor. METHODS: We report on a single center series of 83 patients undergoing surgery for mesenteric ischemia during a 3-year period. Risk factors, clinical presentation, type and timing of imaging studies and their implications for surgical therapy and outcome are analyzed. RESULTS: Hypertension and diabetes were the most common risk factors (68/64% of all patients). Abdominal pain was the most general symptom upon presentation to the surgical unit (73%). Two-phase, contrast-enhanced computed tomography was applied as the standard preoperative imaging modality (correct diagnosis in 69%). Bowel resections were necessary in most patients; approaches to restore blood flow by vascular surgery interventions were applied in 17 patients (20%). The overall morbidity and mortality rate in our study cohort was expectedly high (59% 1 month mortality). CONCLUSION: The diagnosis and surgical treatment of mesenteric ischemia remains a major difficulty. We recommend preoperative CT analysis followed by an aggressive indication for early surgical exploration and bowel resection. An attempt of revascularization is justified for selected patients with limited macrovascular disease.

Multimodality treatment of peritoneal carcinomatosis from colorectal cancer: first results of a new German centre for peritoneal surface malignancies.

BACKGROUND: The presence of peritoneal carcinomatosis arising from colorectal cancer is associated with a poor prognosis. It was the purpose of this study to analyze morbidity, mortality, and survival after major cytoreductive surgery and intraperitoneal chemotherapy. MATERIALS AND METHODS: Thirty-two patients with peritoneal carcinomatosis were operated between April 2004 and June 2006 with the aim of complete macroscopical cytoreduction. All had a primary colorectal carcinoma. Surgery in these patients was followed by hyperthermic intraperitoneal chemotherapy (HIPEC) consisting of mitomycin C and doxorubicin. Data were analyzed retrospectively. RESULTS: Of all patients, 16 had appendix and 16 non-appendiceal colorectal carcinoma. A macroscopically complete cytoreduction was achieved in 24 patients by parietal and visceral peritonectomy procedures. All resections were combined with HIPEC. Overall morbidity was 34%. Most frequent surgical complications were intestinal obstruction (4/32), enteric fistula (2/32), pancreatitis (2/32), and bile leakage (2/32). One patient presented grade 4 renal toxicity. There was no hospital mortality. The median follow-up was 12 months. The 1-year overall survival rate is 96%. All patients after complete cytoreduction are still alive. CONCLUSIONS: Cytoreductive surgery combined with HIPEC is associated with an acceptable morbidity and low mortality. Complete cytoreduction may improve survival, particularly in well-selected patients having a low tumor volume and no extra-abdominal metastases.

Who is willing to take the risk? Assessing the readiness for living liver donation in the general German population.

BACKGROUND: Shortage of donor organs is one of the major problems for liver transplant programmes. Living liver donation is a possible alternative, which could increase the amount of donor organs available in the short term. OBJECTIVE: To assess the attitude towards living organ donation in the general population to have an overview of the overall attitude within Germany. METHODS: A representative quota of people was evaluated by a mail questionnaire (n = 250). This questionnaire had 24 questions assessing the willingness to be a living liver donor for different potential recipients. Factors for and against living liver donation were assessed. RESULTS: Donating a part of the liver was almost as accepted as donating a kidney. The readiness to donate was highest when participants were asked to donate for children. In an urgent life-threatening situation the will to donate was especially high, whereas it was lower in the case of recipient substance misuse. More women than men expressed a higher disposition to donate for their children. Sex, religion, state of health and age of the donor, however, did not influence other questions on the readiness to consider living organ donation. The will for postmortem organ donation positively correlated with the will to be a living organ donor. CONCLUSIONS: The motivation in different demographic subgroups to participate in living liver transplantation is described. Differences in donation readiness resulting from the situation of every donor and recipient are thoroughly outlined. The acceptance for a living liver donation was found to be high - and comparable to that of living kidney donation.

Biophoton emission of human body.

For the first time systematic measurements of the "ultraweak" photon emission of the human body (biophotons) have been performed by means of a photon detector device set up in darkness. About 200 persons have been investigated. In a particular case one person has been examined daily over several months. It turned out that this biophoton emission reflects, (i) the left-right symmetry of the human body; (ii) biological rhythms such as 14 days, 1 month, 3 months and 9 months; (iii) disease in terms of broken symmetry between left and right side; and (iv) light channels in the body, which regulate energy and information transfer between different parts. The results show that besides a deeper understanding of health, disease and body field, this method provides a new powerful tool of non-invasive medical diagnosis in terms of basic regulatory functions of the body.

Ultraweak photon emission in assessing bone growth factor efficiency using fibroblastic differentiation.

Photons participate in many atomic and molecular interactions and changes. Recent biophysical research has shown the induction of ultraweak photons in biological tissue. It is now established that plants, animal and human cells emit a very weak radiation which can be readily detected with an appropriate photomultiplier system. Although the emission is extremely low in mammalian cells, it can be efficiently induced by ultraviolet light. In our studies, we used the differentiation system of human skin fibroblasts from a patient with Xeroderma Pigmentosum of complementation group A in order to test the growth stimulation efficiency of various bone growth factors at concentrations as low as 5 ng/ml of cell culture medium. In additional experiments, the cells were irradiated with a moderate fluence of ultraviolet A. The different batches of growth factors showed various proliferation of skin fibroblasts in culture which could be correlated with the ultraweak photon emission. The growth factors reduced the acceleration of the fibroblast differentiation induced by mitomycin C by a factor of 10-30%. In view that fibroblasts play an essential role in skin aging and wound healing, the fibroblast differentiation system is a very useful tool in order to elucidate the efficacy of growth factors.