Mesenteric granulomas independently predict long-term risk of surgical recurrence in Crohn's disease.

AIM: The risk factors that predict surgical recurrence in Crohn's disease (CD) remain controversial. Postoperative anti-tumour necrosis factor (anti-TNF) therapy might lower recurrence rates whilst the presence of mesenteric granulomas has been postulated to increase the risk. We hypothesized that mesenteric granulomas indicate disease severity and might predict the risk of surgical recurrence, irrespective of immunosuppressive therapy. METHOD: We performed a retrospective review of all consecutive patients undergoing operations for CD between January 2000 and December 2014 at a single tertiary referral centre and assessed the perioperative factors and histological findings at the time of surgery. Surgical recurrence rates and the immunosuppressive regimen were assessed through retrospective chart review and telephone interviews. RESULTS: A total of 274 patients were eligible for analysis. Median follow-up was 8.54 (5.48-14.42) years. A total of 63 patients (23.0%) underwent surgery for recurrent CD after a median of 4.75 (2.10-7.96) years. In final histology, 35 (12.8%) patients had mesenteric granulomas. TNF inhibitors were administered postoperatively in 104 (38.0%) and thiopurines in 137 (50.0%) patients. In univariate analysis, only the presence of mesenteric granulomas [hazard ratio (HR) 1.95; 95% CI 1.05-3.62; P = 0.035] significantly increased the risk for recurrent surgery while postoperative anti-TNF (HR 0.85; 95% CI 0.49-1.50; P = 0.581) or thiopurine therapy (HR 1.03; 95% CI 0.61-1.73; P = 0.916) did not. In multivariate analysis, only the presence of mesenteric granulomas significantly influenced the risk of surgical recurrence (HR 1.94, 95% CI 1.04-3.60; P = 0.037). CONCLUSION: Intestinal and mesenteric granulomas should be differentiated in pathology reports, because mesenteric, but not intestinal, granulomas may be associated with an increased risk of surgical recurrence.

[Future of rheumatologists: what are the perspectives? : Survey of resident physicians in rheumatology in middle Germany]. / Rheumatologin/Rheumatologe in spe: Wie geht es weiter? : Befragung der rheumatologischen Assistenzärzte und -ärztinnen in Mitteldeutschland.

BACKGROUND AND OBJECTIVE: The work environment for rheumatologists has significantly changed over the last years. The healthcare of patients with rheumatic diseases is at risk due to the age structure of specialized rheumatologists in middle Germany and the limited availability of training positions for rheumatologists. In this context, it is important to have detailed information on the resident physicians in rheumatology concerning their own visions regarding their future professional career. MATERIAL AND METHODS: A questionnaire was sent to resident physicians in 25 rheumatology training hospitals in the middle of Germany (Saxony, Saxony-Anhalt and Thuringia). The questionnaire was completed and returned by 27 participants (17 women and 10 men). RESULTS: Most of the participants (60%) aimed to qualify as a specialist in internal medicine followed by a specialization in rheumatology (altogether training for a minimum of 8 years). After finishing training 44% would prefer to work in an outpatient setting while 30% planned to work in a combined outpatient and clinical setting. Of the participants 48% would prefer to work as part-time rheumatologists and 74% (women 94% and men 40%) were interested in employment in an outpatient medical healthcare center. The compatibility of family and work as well as the work-life balance was considered to be highly relevant for the future professional life. CONCLUSION: Less than half of the participants intended to work exclusively in an outpatient setting after completing the training in rheumatology. In addition, the participants preferred a part-time employment with compatibility of professional and private life. Consequently, alternative models of employment should be created in rheumatology to be attractive for future physicians. On the other hand, the study revealed that the independent rheumatological practice has a lower priority for the young rheumatologists taking part in this survey.

[Outpatient specialist medical care : Regulations and practical example of rheumatology]. / Ambulante spezialfachärztliche Versorgung : Regularien und Praxisbeispiel Rheumatologie.

Outpatient specialist medical care targets the intersectoral and interdisciplinary cooperation between hospital physicians and panel physician structures in the diagnostics and treatment of certain disease symptoms under the same framework conditions. The administrative coordination bundled through one person has contributed to an effective placement of applications. In this way the daunting effect of bureaucratic hurdles for potential team members could be intercepted. A close and constructive collaboration of all participants is helpful to come to terms with the new treatment structure and to achieve the anticipated targets for patients, panel physicians and hospitals.

Effect of pathologist's dedication on lymph node detection rate and postoperative survival in colorectal cancer.

AIM: As adjuvant chemotherapy in colorectal cancer relies on the identification of lymph node metastases, the pathologist's dedication may have a considerable influence on postoperative survival. METHOD: The aim of this retrospective study was to assess the impact of the pathologist's dedication on lymph node detection rate and postoperative survival in patients operated on by a single experienced colorectal surgeon within a 5-year period. We assessed 229 patients undergoing total mesorectal excision or complete mesocolic excision by the senior author between 1 January 2009 and 31 December 2013. Pathologists were grouped as 'general pathologist' or 'dedicated pathologist' depending on their dedication/specialization. RESULTS: Dedicated pathologists found statistically significantly more lymph nodes in colorectal specimens than general pathologists [23 (interquartile range 24) vs 14 (interquartile range 11), respectively; P < 0.001]. The detection rate of ≥ 12 lymph nodes per specimen was significantly higher in the dedicated pathologist group [65/74 (87.8%) vs 105/155 (67.7%); P = 0.016]. However, postoperative survival did not differ in the respective subgroups. In the multivariable analysis by Cox proportional hazard model, International Union against Cancer Stage IV was the only factor associated with decreased disease-specific survival (hazard ratio 28.257; 95% CI 3.850-207.386; P = 0.001). CONCLUSION: In our centre, the pathologist's dedication has an impact on lymph node detection rate but does not influence postoperative disease-specific survival.

Genetic risk for squamous cell carcinoma of the nictitating membrane parallels that of the limbus in Haflinger horses.

Squamous cell carcinoma (SCC) is the most common cancer affecting the equine eye, with a higher incidence documented in Haflinger horses. Recently, a missense variant in the gene damage specific DNA binding protein 2 (DDB2, p.Thr338Met) on ECA12 was identified as a risk factor for the development of limbal SCC in Haflinger horses. SCC also occurs on the nictitating membrane; therefore, investigating the role of this missense variant in nictitating membrane SCC is warranted. In this study, a common ancestor was identified among Haflinger horses affected with limbal SCC or with nictitating membrane SCC, thus supporting a recessive risk factor for the development of cancer at both ocular locations. Analysis of genotype data from Haflinger horses with and without nictitating membrane SCC revealed that the same region on ECA12 associated with limbal SCC was also associated with nictitating membrane SCC (P < 2.04 × 10-5 ). Fine mapping of this locus using 25 cases and 49 controls supported the hypothesis that DDB2:c.1013C>T, p.Thr338Met, is a risk factor for nictitating membrane SCC, as 88% of our cases were homozygous for this variant and no other polymorphism was more strongly associated (P = 4.13 × 10-14 ). These data indicate that the genetic risk is the same for the development of both limbal and nictitating membrane SCC in Haflinger horses and validates utilization of genetic testing of the DDB2 variant for both clinical management and the guidance of mating decisions.

[Rituximab for the treatment of poly- and dermatomyositis : Results from the GRAID-2 registry]. / Rituximab zur Behandlung von Poly- und Dermatomyositis : Die Ergebnisse des GRAID-2-Registers.

INTRODUCTION: In the treatment of poly- and dermatomyositis, only a limited number of treatment modalities are established. OBJECTIVE: The goal of the GRAID-2 registry was to study off-label use of biologic drugs for this indication in Germany. PATIENTS AND METHODS: Analysis of the data of the GRAID-2 registry for poly- and dermatomyositis. RESULTS: In 22 of the 23 patients in the GRAID-2 registry, rituximab (RIX) was administered, while 1 patient was given tocilizumab as off-label therapy. The 22 patients who received RIX treatment were analyzed. At the start of treatment, the following active manifestations were present: myositis (n = 18), lung involvement (mainly interstitial lung disease; n = 10), arthritis (n = 10), skin manifestation (n = 9), and Raynaud syndrome (n = 5). Nine of the patients were Jo-1-antibody positive. All patients had previous treatments with multiple conventional immunosuppressive drugs. Treatment with RIX was given as infusions of 1 g i. v., which were repeated after 2 weeks. Patients received a mean of 3.09 ± 2.27 infusions (equivalent to 1.5 cycles of 2 × 1 g, max. 5 cycles). Tolerability of RIX treatment was rated as very good in 16 of 22 patients (72%), good in 5 (23%), and moderate in 1 (5%). In all, 27 adverse events were documented, with the majority being infections, whereby 2 severe infections occurred (6.59 per 100 patient-years). Eighty six percent of the patients showed complete remission of their myositis and 79% of their arthritis. The mean value of creatinine kinase in plasma fell from 1505 ± 2534 U/l before the start of treatment to 39 ± 134 U/l at the last visit. Regarding lung involvement, 1 of 10 of the patients showed complete and 6 of 10 partial remissions. In 2 of 10 patients, lung disease was stable during treatment. CONCLUSION: RIX is the preferred off-label biologic drug for poly- and dermatomyositis in Germany. In spite of a strongly pretreated group of patients, the tolerability is acceptable, although the patient number in this investigation is small. Moreover, the results lead to the assumption that the majority of the patients had a good or even very good therapeutic response to RIX.

[Off-label biologic therapy of ANCA-associated and non-ANCA-associated small-vessel vasculitis : Efficacy and safety analysis of a national registry (GRAID2)]. / Off-label-Biologikatherapie von ANCA-assoziierten und nicht-ANCA-assoziierten Kleingefäßvaskulitiden : Wirksamkeits- und Sicherheitsanalyse eines nationalen Registers (GRAID2).

OBJECTIVE: To evaluate the clinical efficacy and safety of off-label biological therapies in patients with ANCA-associated vasculitis (AAV) and non-ANCA-associated small-vessel vasculitis (nAAV) in clinical practice. METHODS: The German Registry in Autoimmune Diseases 2 (GRAID2) is a national, retrospective, non-interventional, multicentre observational study (August 2006 until December 2013) on patients with autoimmune diseases refractory to standard immunosuppressive therapy treated with off-label biologicals. RESULTS: Data from 64 patients (20.6% of all GRAID2 patients) were collected: 54 patients (84.4%) had ANCA-associated vasculitis (AAV) and 10 patients (15.6%) had non-ANCA-associated small-vessel vasculitis (nAAV). Of the AAV patients, 96.3% were treated off-label with rituximab (RTX) and 3.7% with tumor necrosis factor alpha (TNFα)-inhibitors. Of patients with nAAV, 30% were treated with RTX, 60% with TNFα-inhibitors, and 10% with tocilizumab. The main reasons for off-label biological treatment in AAV patients were pulmonary, renal, or ear, nose, and throat involvement. These manifestations clearly improved in most patients after off-label biological therapy was initiated. Daily glucocorticoid dosage could be reduced. The off-label biological therapy was generally well tolerated. In AAV patients, 4.18 severe infections per 100 patient years were observed. There was one death in the nAAV group caused by fungal infection and ileus. A correlation between this fatality and RTX treatment was regarded as possible. CONCLUSION: Safety and efficacy of off-label RTX-treatment in AAV-patients could be assessed in the GRAID2 data. Results point to good efficacy and safety of RTX in this special patient cohort and support the approval of RTX for AAV induction therapy.

[Safety and efficacy of off-label use of biologic therapies in patients with inflammatory rheumatic diseases refractory to standard of care therapy : Data from a nationwide German registry (GRAID2)]. / Sicherheit und Wirksamkeitshinweise zum Off-label-Einsatz von Biologikatherapien nach Versagen konventioneller Therapien bei Patienten mit entzündlich rheumatischen Erkrankungen : Ergebnisse eines nationalen Registers (GRAID2).

BACKGROUND: The German Registry of Autoimmune Diseases 2 (GRAID2) is a retrospective, non-interventional, multicenter registry study collecting data from patients with inflammatory, mainly rheumatic diseases refractory to standard of care therapy and treated with an off-label biologic therapy. The retrospective documentation comprised case history, diagnosis, course of disease (including safety and global efficacy). The objective was to evaluate the global clinical outcome and safety of off-label biologic therapy in clinical practice. RESULTS: Data from 311 patients with an overall observation period of 338.5 patient-years were collected. The mean patients age was 47.8 years with 56.9% females. The most frequently documented diagnoses comprised rejection prophylaxis/therapy after renal transplantation (NTX, 18.3%), ANCA-vasculitides (17.4%), systemic lupus erythematosus (SLE, 10.3%), autoinflammatory fever syndromes (8.4%), autoimmune myositis (7.4%) and pemphigus (5.8%). Documented biologic therapies included rituximab (RTX, 70.1%), tocilizumab (TCZ, 9.3%), infliximab (IFX, 7.1%), anakinra (ANK, 5.5%), adalimumab (ADA, 3.5%), etanercept (ETA, 2.3%) and certolizumab (CTZ, 0.6%). After initiation of off-label biologic treatment, tolerability was assessed by the physicians as "very good"/"good" in 95.5%. Altogether, 275 adverse events were documented and of these, 104 were classified as serious adverse events and occurred in 62 patients. In 19 of these patients severe infections (30.6%) were documented, resulting in a rate of 5.6 severe infections per 100 patient years. A total of six deaths were documented, while five of these cases were rated as not related to the biologics treatment. Notably, the use of RTX in patients with small vessel vasculitides and of TCZ in patients with large vessel vasculitides prior to their approval support their relevance in clinical management of patients with severe diseases. CONCLUSION: The results of this registry together with data of GRAID1 provide evidence that use of off-label biologic therapies in patients with inflammatory rheumatic diseases refractory to conventional treatment did not result in any new safety signal already known for these compounds or subsequently shown by clinical trials in certain entities.

Regulatory T Cells Promote Natural Killer Cell Education in Mixed Chimeras.

Therapeutic administration of regulatory T cells (Tregs) leads to engraftment of conventional doses of allogeneic bone marrow (BM) in nonirradiated recipient mice conditioned with costimulation blockade and mammalian target of rapamycin inhibition. The mode of action responsible for this Treg effect is poorly understood but may encompass the control of costimulation blockade-resistant natural killer (NK) cells. We show that transient NK cell depletion at the time of BM transplantation led to BM engraftment and persistent chimerism without Treg transfer but failed to induce skin graft tolerance. In contrast, the permanent absence of anti-donor NK reactivity in mice grafted with F1 BM was associated with both chimerism and tolerance comparable to Treg therapy, implying that NK cell tolerization is a critical mechanism of Treg therapy. Indeed, NK cells of Treg-treated BM recipients reshaped their receptor repertoire in the presence of donor MHC in a manner suggesting attenuated donor reactivity. These results indicate that adoptively transferred Tregs prevent BM rejection, at least in part, by suppressing NK cells and promote tolerance by regulating the appearance of NK cells expressing activating receptors to donor class I MHC.

The Immunosuppressive Effect of CTLA4 Immunoglobulin Is Dependent on Regulatory T Cells at Low But Not High Doses.

B7.1/2-targeted costimulation blockade (CTLA4 immunoglobulin [CTLA4-Ig]) is available for immunosuppression after kidney transplantation, but its potentially detrimental impact on regulatory T cells (Tregs) is of concern. We investigated the effects of CTLA4-Ig monotherapy in a fully mismatched heart transplant model (BALB/c onto C57BL/6). CTLA4-Ig was injected chronically (on days 0, 4, 14, and 28 and every 4 weeks thereafter) in dosing regimens paralleling clinical use, shown per mouse: low dose (LD), 0.25 mg (≈10 mg/kg body weight); high dose (HD), 1.25 mg (≈50 mg/kg body weight); and very high dose (VHD), 6.25 mg (≈250 mg/kg body weight). Chronic CTLA4-Ig therapy showed dose-dependent efficacy, with the LD regimen prolonging graft survival and with the HD and VHD regimens leading to >95% long-term graft survival and preserved histology. CTLA4-Ig's effect was immunosuppressive rather than tolerogenic because treatment cessation after ≈3 mo led to rejection. FoxP3-positive Tregs were reduced in naïve mice to a similar degree, independent of the CTLA4-Ig dose, but recovered to normal values in heart recipients under chronic CTLA4-Ig therapy. Treg depletion (anti-CD25) resulted in an impaired outcome under LD therapy but had no detectable effect under HD therapy. Consequently, the immunosuppressive effect of partially effective LD CTLA4-Ig therapy is impaired when Tregs are removed, whereas CTLA4-Ig monotherapy at higher doses effectively maintains graft survival independent of Tregs.

Interactions between Metopolophium festucae cerealium (Hemiptera: Aphididae) and Barley yellow dwarf virus (BYDV-PAV).

Interactions between an invasive aphid, Metopolophium festucae (Theobald) subsp. cerealium, and Barley yellow dwarf virus (BYDV-PAV) were studied under laboratory conditions. M. festucae cerealium is an economic pest of wheat and barley that has recently been found in high population densities in wheat in the Pacific Northwest of the United States. BYDV-PAV is the most prevalent and injurious species of BYDV worldwide and in the Pacific Northwest. Although M. festucae sensu stricto (Theobald 1917) has been reported previously as a vector of some BYDV isolates, there is no confirmed transmission of BYDV by M. festucae cerealium. Two experiments examined the ability of M. festucae cerealium to transmit BYDV-PAV. The first used single aphids caged to indicator plants of a BYDV-susceptible winter wheat cultivar and the second used multiple aphids on each test plant. M. festucae cerealium did not transmit BYDV-PAV in either experiment, whereas transmission by a known BYDV vector, Rhopalosiphum padi L., was consistently high (≥ 93%). A third experiment compared the intrinsic growth rate, days until first reproduction and daily reproduction by M. festucae cerealium on sham-inoculated and BYDV-PAV-infected wheat, but detected no differences. The findings are reviewed in light published data on M. festucae species, BYDV transmission, and the potential pest status of this new invading aphid.

Nodular epitheloid sarcoma of the upper limb. A case report and review of the literature.

Epitheloid sarcoma is a rare malignant soft tissue sarcoma. We present a 36-year-old male patient with a primary tumour on his wrist and subcutaneous spread in a sporotrichoid pattern along the upper extremity. Early surgical treatment with micrographic control of all margins provides best long term outcome as long as a solitary lesion is present. In case of cutaneous and internal spread of the disease treatment options are only palliative. Early diagnosis, therefore, is most crucial.

Outcomes for split-thickness skin transplantation in high-risk patients using octenidine.

Skin transplantation is a commonly used surgical technique; however, the complication rate, including postoperative infection and delayed wound healing due to inefficient perfusion, is significantly higher in patients suffering from comorbidities. Hence, a subsequent repeat procedure is often necessary. In this report, two case studies are presented in which an octenidine-based antiseptic is used with a tie-over dressing (TOD) instead of povidone iodine (PVP-iodine), following a split-thickness skin graft. The two patients selected were deemed to be at high risk of impaired wound healing due to comorbidities. The first patient, a confirmed smoker with diabetes, presented with a nodular melanoma that was resected and covered with a split-thickness skin graft. After 5 days of negative pressure wound therapy as a TOD, in combination with PVP-iodine, the graft became necrotic. A second split-thickness skin graft was performed and an antiseptic regimen with octenidine in combination with the same TOD resulted in a completely healed transplant. The second patient, also a confirmed smoker with diabetes and receiving oral corticosteroid treatment, was diagnosed with a skin necrosis on her leg. Following the split-thickness skin graft, octenidine and TOD were applied. The patient's skin graft completely healed without any adverse events. These two case studies indicate that the combination of octenidine and TOD following split-thickness skin transplantation is safe, well-tolerated and appears to have positive benefits in the reconstruction of defects in patients with impaired wound healing.

Lung Sealing with the Sandwich-Technique: A New Surgical Method to Deal with the Emphysematous Lung.

UNLABELLED: The persistent air leak is a common and sometimes difficult to manage complication after major pulmonary resections. Especially in cases with lung emphysema spontaneous sealing of the lung surface under conservative therapy can be prolonged or even fail and a reoperation to close the damaged visceral pleura might be necessary. An ideal surgical solution to deal with this problem is not known, all of the techniques have advantages but also limitations and additional operations should be avoided in this group of frail patients. In this paper a new surgical method to seal the lung surface is presented based on two exemplary cases and our clinical experience. Basically, two stripes of fleece bounded fibrin based sealant are put on the visceral pleura parallel to the wound, which will be then closed by multiple stitches of absorbable suture line inserted through the stripes. Afterwards, a second layer of the same sealant will be placed over it to cover the suture with a narrow overlapping in all directions to the adjacent visceral pleura (Sandwich-Technique). In our experience, this technique can be used to successfully prevent or treat persistent air leaks especially in patients with lung emphysema in whom otherwise treatment options are limited. ABBREVIATIONS: VATS = video-assisted thoracoscopic surgery POD = postoperative day LVRS = lung volume reduction surgery FEV1 = forced expiratory volume in the first second DLCO = diffusing capacity of the lung for carbon monoxide.

Clinical outcomes and safety of rituximab treatment for patients with systemic lupus erythematosus (SLE) - results from a nationwide cohort in Germany (GRAID).

OBJECTIVE: The objective of this article is to evaluate the safety and clinical outcome of rituximab treatment in systemic lupus erythematosus (SLE) patients refractory to standard of care therapy in a real-life setting in Germany. METHODS: The GRAID registry included patients with different autoimmune diseases who were given off-label treatment with rituximab. Data on safety and clinical response were collected retrospectively. In SLE patients, clinical parameters included tender and swollen joint counts, fatigue, myalgia, general wellbeing, Raynaud's and the SLEDAI index. Laboratory tests included dsDNA antibody titres, complement factors, hematologic parameters and proteinuria. Finally, the investigators rated their patients as non-, partial or complete responders based on clinical grounds. RESULTS: Data from 85 SLE patients were collected, 69 female and 16 male, with a mean disease duration of 9.8 years. The mean follow-up period was 9.6 ± 7.4 months, resulting in 66.8 patient years of observation. A complete response was reported in 37 patients (46.8%), partial response in 27 (34.2%), no response in 15 (19.0%). On average, major clinical as well as laboratory efficacy parameters improved substantially, with the SLEDAI decreasing significantly from 12.2 to 3.3 points. Concerning safety, one infusion reaction leading to discontinuation of treatment occurred. Infections were reported with a rate of 19.5 (including six severe infections) per 100 patient years. CONCLUSION: With the restrictions of a retrospective data collection, the results of this study confirm data of other registries, which suggest a favourable benefit-risk ratio of rituximab in patients with treatment-refractory SLE.

[Leg ulcers]. / Ulcus cruris.

The lower leg is in particular prone to the development of ulceration. Many different causes may lead to ulceration. Thus, a thorough diagnosis is mandatory, and a biopsy is often required. By far the most common type is the classical venous ulcer due to chronic venous insufficiency, located at the medial ankle. A more complicated-and more difficult to treat-type of venous ulcer is arthrogenic congestion syndrome with its extreme variant of a "legging" ulcer. In cases with severe peripheral arterial disease, an arterial ulcer may develop. The hypertensive ulcer Martorell is associated with arterial hypertension and diabetes; the underlying pathology is occlusion of arteriolar vessels. A typical diabetic ulceration is the necrobiosis lipoidica. Important differential diagnoses of leg ulceration include pyoderma gangrenosum and the calciphylactic ulcer. Due to a long-standing course, an ulceration may turn malignant. Vice versa, ulceration may occur as sign of a primary malignant lesion.

[Foot lesions]. / Fußläsionen.

The foot is the target organ of a variety of internal diseases. Of upmost importance is the diabetic foot syndrome (DFS). Its complex pathophysiology is driven by the diabetic neuropathy, a vastly worsening effect is contributed by infection and ischemia. Seemingly localised lesions have the potential for phlegmone and septicaemia if not diagnosed and drained early. The acral lesions of peripheral artery occlusive disease (PAOD) have unique features as well. However, their life-threatening potential is lower than that of DFS even if the limb is critical. Notably, isolated foot lesions with a mere venous cause may arise from insufficient perforator veins; the accompanying areas of haemosiderosis will lead the diagnostic path. Cholesterol embolization (blue toe syndrome, trash foot) elicits a unique clinical picture and will become more frequent with increasing numbers of catheter-based procedures. Finally, descriptions are given of podagra and of foot mycosis as disease entities not linked to perfusion. The present review focuses on the depiction of disease and its diagnosis, leaving therapeutic considerations untouched.

[Leg pain]. / Das schmerzhafte Bein.

Leg pain is a very common complaint in clinical medicine which deserves thorough investigation. All tissues of the lower leg are able to cause pain, each of them by different pathomechanisms. In the current review, all the different types of tissue, i.e., spine, neural plexus, peripheral nerves, muscles, and vasculature, are systematically covered. The different disease entities are explained in terms of pathophysiology and clinical picture. Diagnostic measures and pathways are sketched, as well as therapeutic approaches in some instances. Diseases of the bone and joint are omitted since they are the subject of orthopedic surgery.

[Leg discoloration]. / Das verfärbte Bein.

Many patients present with discolouration of the legs or with non-ulcerating skin lesions, the most frequent causes being chronic venous insufficiency or other chronic or acute states of congestion. Erysipelas (cellulitis) is also a frequent example of a bacterial skin infection. A complex differential diagnosis arises from all types of immune-mediated skin lesions, opening up the broad spectrum of inflammatory systemic disease, such as vasculitis and sarcoidosis. Livedo like lesions and skin involvement in borreliosis are challenging to classify but of considerable clinical importance. The present review focuses on the description of underlying diseases as well as on diagnosis and differential diagnosis. Therapeutic considerations are discussed in less detail.

[Leg swelling]. / Das geschwollene Bein.

Leg swelling is an extremely frequent symptom with a broad variety of largely differing causes. The most important mechanisms behind the symptom include venous and lymphatic pathology, volume overload, increased capillary permeability, and lowered oncotic pressure. Therefore, the most frequent diseases associated with leg swelling are deep vein thrombosis and chronic venous insufficiency, primary or secondary lymphedema, cardiac failure, hypoproteinemia due to liver or renal failure, idiopathic cyclic edema, and drug-induced edema. Lipedema as a misnomer represents an important differential diagnosis. History and physical examination, when based on a sound knowledge of the diseases of interest, enable a conclusive diagnosis in most cases. Additional test are required in only a minority of patients. The present review discusses pathophysiology and clinical features of the most prevalent types of leg swelling. Finally, a brief guide to differential diagnosis is given.