Treatment outcome of the Masquelet technique in 195 infected bone defects-A single-center, retrospective case series.

BACKGROUND: The Masquelet technique is a surgical procedure for the reconstruction of bone defects. During the first step, an osteosynthetically stabilized defect is filled with a cement spacer. The spacer induces a foreign body membrane, called a Masquelet membrane. In a follow-up procedure, the spacer is replaced by a bone graft, which ossifies in the subsequent phase. MATERIAL AND METHODS: A total of 171 patients with 195 septic bone defects on the extremities that had been treated with the Masquelet procedure at the BG Klinikum in Hamburg, Germany, from 2011 to 2021 were retrospectively analysed, comparing patients who reached full weight and load bearing on the affected extremity to those who failed to do so. Defect size and configuration, microbiological results and treatment methods as well as comorbidities and epidemiologic data were analysed for factors influencing the treatment outcome. RESULTS: In all, 113[66%] of the patients were male, and 58[34%] were female, with an age distribution of 52 +/-16 years. Out of 171 patients, 24 patients had two defects. The number of patients that reached full weight bearing was 152[89%], the follow-up period was 2 +/-1 years (median +/- SD). Full weight bearing capability was negatively by the defect size as defects >62 mm tended to be less likely to reach full weight bearing than smaller defects. A secondary stabilization with an internal stabilization was applied in 58[34%] of all patients and positively influenced the attainment of full weight and load bearing. DISCUSSION: With 171 patients and 195 septic bone defects treated at a single centre with the Masquelet Technique, this study represents a comparably large cohort. Demographics, defect characteristics and treatment outcomes did not differ from those of other cohorts described in the literature. Defects larger than 62 mm showed lower chances to reach full weight bearing and can be defined as "critical defect size" for the Masquelet technique based on our data.

[Therapeutic strategies for joint infections]. / Therapiestrategie bei Gelenkinfektionen.

Joint infections represent a severe complication that results in irreversible joint destruction when left untreated or treated inadequately. The reasons for joint infections include endogenous hematological and exogenous factors. In the patient cohort described here, the empyema was almost exclusively acquired through iatrogenic measures (e.g. arthroscopic operations, punctures and intra-articular infections) or as a result of fractures close to the joint and penetrating injuries. Acute joint empyema is an orthopedic emergency, which must be immediately surgically treated because irreversible cartilage damage can rapidly occur due to the pathophysiological process. Acute joint empyema must be treated arthroscopically. Chronic empyema must be assumed when the clinical symptoms last for more than 7 days. Chronic empyema should be treated by arthrotomy, synovectomy and removal of extraneous material including cruciate ligament replacement material.

Abdominal Wall Transplantation: Skin as a Sentinel Marker for Rejection.

Abdominal wall transplantation (AWTX) has revolutionized difficult abdominal closure after intestinal transplantation (ITX). More important, the skin of the transplanted abdominal wall (AW) may serve as an immunological tool for differential diagnosis of bowel dysfunction after transplant. Between August 2008 and October 2014, 29 small bowel transplantations were performed in 28 patients (16 male, 12 female; aged 41 ± 13 years). Two groups were identified: the solid organ transplant (SOT) group (n = 15; 12 ITX and 3 modified multivisceral transplantation [MMVTX]) and the SOT-AWTX group (n = 14; 12 ITX and 2 MMVTX), with the latter including one ITX-AWTX retransplantation. Two doses of alemtuzumab were used for induction (30 mg, 6 and 24 h after reperfusion), and tacrolimus (trough levels 8-12 ng/mL) was used for maintenance immunosuppression. Patient survival was similar in both groups (67% vs. 61%); however, the SOT-AWTX group showed faster posttransplant recovery, better intestinal graft survival (79% vs. 60%), a lower intestinal rejection rate (7% vs. 27%) and a lower rate of misdiagnoses in which viral infection was mistaken and treated as rejection (14% vs. 33%). The skin component of the AW may serve as an immune modulator and sentinel marker for immunological activity in the host. This can be a vital tool for timely prevention of intestinal graft rejection and, more important, avoidance of overimmunosuppression in cases of bowel dysfunction not related to graft rejection.

[Classification of haematogenous and post-traumatic osteomyelitis]. / Klassifikation der Osteomyelitis und Osteitis.

A classification of osteomyelitis must reflect the complexity of the disease and, moreover, provide conclusions for the treatment. The classification is based on the following eight parameters: source of infection (OM [osteomyelitis]/OT [post-traumatic OM]), anatomic region, stability of affected bone (continuity of bone), foreign material (internal fixation, prosthesis), range of infection (involved structures), activity of infection (acute, chronic, quiescent), causative microbes (unspecific and specific bacteria, fungi) and comorbidity (immunosuppressive diseases, general and local). In the long version of the classification, which was designed for scientific studies, the parameters are named by capital letters and specified by Arabic numbers, e.g., an acute, haematogenous osteomyelitis of a femur in an adolescent with diabetes mellitus, caused by Staphylococcus aureus, multi-sensible is coded as: OM2 Lo33 S1a M1 In1d Aa1 Ba2a K2a. The letters and numbers can be found in clearly arranged tables or calculated by a freely available grouper on the internet (www.osteomyelitis.exquit.net). An equally composed compact version of the classification for clinical use includes all eight parameters, but without further specification. The above-mentioned example in the compact version is: OM 3 S a Ba2 K2. The short version of the classification uses only the first six parameters and excludes causative microbes and comorbidity. The above mentioned example in the short version is: OM 3 S a. The long version of the classification describes an osteomyelitis in every detail. The complexity of the patient's disease is clearly reproducible and can be used for scientific comparisons. The for clinical use suggested compact and short versions of the classification include all important characteristics of an osteomyelitis, can be composed quickly and distinctly with the help of tables and provide conclusions for the individual treatment. The freely available grouper (www.osteomyelitis.exquit.net) creates all three versions of the classification in one step.

Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels.

Acute graft-versus-host disease (GvHD) limits the applicability of allogeneic hematopoietic cell transplantation for the treatment of leukemia. GvHD occurs as a consequence of multiple activating events in antigen-presenting cells (APCs) and T cells (Tcs). Spleen tyrosine kinase (Syk) is an intracellular non-receptor tyrosine kinase involved in multiple signaling events of immune cells. Therefore, we hypothesized that Syk may be a promising target to inhibit GvHD, which involves activation of different immune cell populations. In vivo expansion of luciferase(+) donor Tcs in mice developing GvHD was reduced by treatment with the Syk inhibitor Fostamatinib, which led to increased survival and reduced histologically confirmed GvHD severity. Importantly, in vivo and in vitro cytotoxicity against leukemia target cells and anti-murine cytomegalovirus immune responses were not impacted by Fostamatinib. In APCs Syk inhibition reduced the expression of costimulatory molecules and disrupted cytoskeletal organization with consecutive APC migratory defects in vitro and in vivo while phagocytic activity remained intact. On the basis of these immunomodulatory effects on different cell populations, we conclude that Syk targeting in alloantigen-activated Tcs and APCs with pharmacologic inhibitors, already applied successfully in anti-lymphoma therapy, has clinical potential to reduce GvHD, especially as anti-leukemia and anti-viral immunity were preserved.

[Definition of the Diagnosis Osteomyelitis-Osteomyelitis Diagnosis Score (ODS)]. / Zur Definition der Diagnose Osteomyelitis - Osteomyelitis-Diagnose-Score (ODS).

AIM: The disease "osteomyelitis" is characterised by different symptoms and parameters. Decisive roles in the development of the disease are played by the causative bacteria, the route of infection and the individual defense mechanisms of the host. The diagnosis is based on different symptoms and findings from the clinical history, clinical symptoms, laboratory results, diagnostic imaging, microbiological and histopathological analyses. While different osteomyelitis classifications have been published, there is to the best of our knowledge no score that gives information how sure the diagnosis "osteomyelitis" is in general. METHOD: For any scientific study of a disease a valid definition is essential. We have developed a special osteomyelitis diagnosis score for the reliable classification of clinical, laboratory and technical findings. The score is based on five diagnostic procedures: 1) clinical history and risk factors, 2) clinical examination and laboratory results, 3) diagnostic imaging (ultrasound, radiology, CT, MRI, nuclear medicine and hybrid methods), 4) microbiology, and 5) histopathology. RESULTS: Each diagnostic procedure is related to many individual findings, which are weighted by a score system, in order to achieve a relevant value for each assessment. If the sum of the five diagnostic criteria is 18 or more points, the diagnosis of osteomyelitis can be viewed as "safe" (diagnosis class A). Between 8-17 points the diagnosis is "probable" (diagnosis class B). Less than 8 points means that the diagnosis is "possible, but unlikely" (class C diagnosis). Since each parameter can score six points at a maximum, a reliable diagnosis can only be achieved if at least 3 parameters are scored with 6 points. CONCLUSION: The osteomyelitis diagnosis score should help to avoid the false description of a clinical presentation as "osteomyelitis". A safe diagnosis is essential for the aetiology, treatment and outcome studies of osteomyelitis.

Tumor necrosis factor alpha inhibitors as immunomodulatory antirejection agents after intestinal transplantation.

We reported the successful administration of infliximab for late-onset OKT3-resistant rejection in two patients, who presented persistent ulcerative inflammation of the ileal graft after intestinal transplantation (ITX). Based on this experience, the present study demonstrated our long-term experience with infliximab for different types of rejection-related and inflammatory allograft alterations. Infliximab administration (5 mg/kg body weight (BW)) was initiated at a mean of 18.2 ± 14.1 months after transplantation. The number of administrations per patient averaged 8.4 ± 6.7. Repeat dosing was timed according to clinical signs and graft histology in addition to serum-levels of tumor necrosis factor alpha (TNFα), lipopolysaccharide binding protein (LBP) and C-reactive protein (CRP). Infliximab was successful in the following patients: patients with late-onset OKT3- and steroid-refractory rejection who presented persistent ulcerative alterations of the ileal graft (n = 5), patients with ulcerative ileitis/anastomositis, who did not show typical histological rejection signs (n = 2), and one patient with early-onset OKT3-resistant rejection. Infliximab was not successful in one patient with early-onset OKT3-resistant rejection that was accompanied by treatment-refractory humoral rejection. In conclusion, infliximab can expand therapeutic options for late-onset OKT3- and steroid-refractory rejection and chronic inflammatory graft alterations in intestinal allograft recipients.

[Medium-term results of surgical treatment for osteitis of the clavicle]. / Mittelfristige Ergebnisse der operativen Behandlung bei Claviculaosteitis.

AIM: Osteitis of the clavicle is rare and not well described in the international literature. We describe a concept of surgical treatment with medium-term observations. METHOD: A total of 22 patients (12 women, 10 men; BMI Ø 24.6 kg/m(2), age Ø 48 years) with osteitis of the clavicle were included in the series. The treatment regime consisted of a surgical approach. Data collection was prospective. Data gathered preoperatively and at follow-up included clinical examination, laboratory findings, radiographs and the Constant scoring system. The mean follow-up period was 13.3 (3-53) months. RESULTS: The described surgical concept was able to permanently eliminate infection in all cases studied. Surgical revisions were required in six patients. The average Constant score showed a significant increase from 66 to 84 at follow-up. Patients also showed good functional results after total resection of the clavicle. CONCLUSION: The reported treatment regime provides reliable results in terms of eliminating infection with good clinical results. Neighboring joints were frequently also involved in the infection and needed to be surgically addressed.

Epithelioid angiosarcoma of the scapula.

Epithelioid angiosarcoma is a rare variation of an angiosarcoma and its localization in the bone is exceptionally infrequent. This report presents the case of a 48-year-old male with an epithelioid angiosarcoma of the scapula. In CT and MRI scans an inhomogeneous tumour with osseous destructions, lytic areas, central necrosis and marginal hyperperfusion was observed. The bordering skeletal muscles were already infiltrated. The tumour was treated initially with neoadjuvant chemotherapy, followed by dose escalation, peripheral blood stem cell transplantation and resection of the lesion. Despite advanced local tumour stage at initial presentation, the patient is in complete remission.

Pulmonary fat embolism after reamed and unreamed nailing of femoral fractures.

BACKGROUND: To determine whether reamed or unreamed intramedullary nailing of femoral fractures results in higher incidence of pulmonary fat embolism, three different methods of intramedullary nailing were compared in sheep. To analyze the presence of bone marrow fat embolism in pulmonary arteries, histological evaluation was undertaken using a quantitative computer-assisted measurement system. METHODS: In this experimental model of 27 female Swiss alpine sheep, an osteotomy of the proximal femur was conducted in each animal. Then, the animals were divided into three groups according to the method of treatment: two different reamed intramedullary nailing techniques and an unreamed nailing technique were used. In the first group "ER" (experimental reamer; n=9), the nail was inserted after reaming with an experimental reamer; in the second group "CR" (conventional reamer; n=7), the intramedullary nail was inserted after reaming with the conventional AO-reamer. In the third group "UN" (unreamed; n=8) unreamed nailing was performed. During the operation procedure intramedullary pressure was measured in the distal fragment. After sacrificing the animals, quantitative histological analyses of bone marrow fat embolism in pulmonary arteries were done using osmium tetroxide fixation and staining of the fat. RESULTS: The measurement of intramedullary pressure showed significantly lower values for reamed nailing than for the unreamed technique. The quantitative histological evaluation of lung vessels concerning bone marrow fat embolism revealed a statistically significant difference between reamed and unreamed insertion of the nail: 7.77%±6.93 (ER) and 6.66%±5.61 (CR) vs. 16.25%±10.05 (UN) (p<0.05) of the assessed lung vessels were filled with fat emboli. However, no difference was found between the traditional and experimental reamer. CONCLUSIONS: Intramedullary nailing after reaming is a safe procedure with low systemic embolisation when compared to the unreamed insertion of the nail.

Benign fibrous histocytoma of the distal radius: a report of a case and a review of the literature.

Benign fibrous histocytoma of bones is a very rare tumour and only a few cases have been reported. We report a case of 40-year-old patient with no significant previous medical history who presented with a painful lesion in his right wrist joint. Incision biopsy was done and there was a histological picture similar to a metaphyseal fibrous defect (non-ossifying fibroma). This was managed with excision of the lesion and filling the defect with cancellous and cortical bone grafts from the left iliac bone. To our knowledge, this is the second case report of a benign fibrous histocytoma involving the distal radius in adult. In this case report, we review similar cases in the literature and discuss the differential diagnoses of this lesion.

Posttraumatic severe infection of the ankle joint - long term results of the treatment with resection arthrodesis in 133 cases.

Although there is a clear trend toward internal fixation for ankle arthrodesis, there is general consensus that external fixation is required for cases of posttraumatic infection. We retrospectively evaluated the technique and clinical long term results of external fixation in a triangular frame for cases of posttraumatic infection of the ankle. From 1993 to 2006 a consecutive series of 155 patients with an infection of the ankle was included in our study. 133 cases of the advanced "Gächter" stage III and IV were treated with arthrodesis. We treated the patients with a two step treatment plan. After radical debridement and sequestrectomy the malleoli and the joint surfaces were resected. An AO fixator was applied with two Steinmann-nails inserted in the tibia and in the calcaneus and the gap was temporary filled with gentamicin beads as the first step. In the second step we performed an autologous bone graft after a period of four weeks. The case notes were evaluated regarding trauma history, medical complaints, further injuries and illnesses, walking and pain status and occupational issues. Mean age at the index procedure was 49.7 years (18-82), 104 patients were male (67.1%). Follow up examination after mean 4.5 years included a standardised questionnaire and a clinical examination including the criteria of the AOFAS-Score and radiographs. 92.7% of the cases lead to a stable arthrodesis. In 5 patients the arthrodesis was found partly-stable. In six patients (4,5%) the infection was not controllable during the treatment process. These patients had to be treated with a below knee amputation. The mean AOFAS score at follow up was 63.7 (53-92). Overall there is a high degree of remaining disability. The complication rate and the reduced patient comfort reserve this method mainly for infection. Joint salvage is possible in the majority of cases with an earlier stage I and II infection.

[Pseudo-arthroses]. / Pseudarthrosen.

Pseudo-arthroses are disorders of fracture healing after conservative or operative treatment of fractures which are older than 6 months. Decisive for a targeted therapy is a differentiation between aseptic and septic or atrophic, oligotrophic or hypertrophic pseudo-arthrosis. The operative principals include revitalization of atrophic bone fragments, stabilizing reosteosynthesis for instability and the treatment of infection by transformation of a septic into a stabilized or aseptic pseudo-arthrosis.

[Principles of OSG arthrodesis in cases of joint infection]. / Prinzipien der OSG-Arthrodese bei Gelenkinfekt.

A chronic empyema of the ankle joint often develops after an open fracture or surgery. In the case of the destruction of the joint due to an infection, an arthrodesis should be performed. Normally we use an external fixator with two bone-nails placed into the calcaneus and two into the tibia. The arthrodesis is distracted and Septopal is permanently implemented. At 4-6 weeks after surgery the Septopal is removed, with distraction being reduced and a cancellous bone-graft taken from the dorsal iliac crest is performed to fill the bony defect. After bone healing, the external fixator is removed and the patient mobilized in a brace. Initially, weight-bearing is limited to 10 kg but is increased gradually to full weight. The brace is used for 6-9 months; later the patient is mobilized in orthopaedic shoes. In difficult cases, also in combination with a malposition which has to be corrected or a lengthening of the lower limb, we use the Ilizarov fixator. From 1993 to 2003 we performed arthrodeses of the ankle joint due to infectious destruction in 107 cases. In 82.2%, the empyema was caused by a fracture of the ankle joint and the following treatment. In 58% of the patients, we saw associated diseases such as obesity, alcohol abuse, diabetes and malposition of the foot. In 55% we found Staphylococcus aureus. In 86%, we used the external AO-fixator, in 14% the Ilizarov fixator. The patient retained the fixator for an average of 128 days. In our study, 92.1% of the 101 patients who had completed therapy showed a good stability an average of 4.5 years after the arthrodesis. In 5% we found partial stability, while three patients had to be amputated. In 57 patients (56.4), an arthrosis of the tarsal bones was found, and 38 patients (54.3%) of the 70 patients who at the time of the arthrodesis were still working could return to work.

Blockers of the slowly delayed rectifier potassium IKs channel: potential antiarrhythmic agents.

Prolongation of the cardiac action potential and the effective refractory period is a proven principle to prevent cardiac arrhythmias, especially under conditions when the action potential is shortened. Several approaches have been made to achieve this effect selectively and without proarrhythmic side effects. Besides the blockade of the cardiac sodium channel, blockade of the delayed rectifier potassium channel I(K) was attempted to achieve this goal. After the discovery that the delayed rectifier potassium channel I(K) consists of two distinct channels, the rapidly and the slowly delayed rectifier potassium channel I(Kr) and I(Ks) respectively, blockers for these targets were looked for. But most of the described blockers of I(K), like dofetilide and D-sotalol, are highly selective and potent I(Kr) channel blockers or have only a side-activity on the I(Ks) channel, as described for azimilide. These compounds have shown their efficacy in terminating atrial or ventricular fibrillation under certain circumstances, but they also have shown high risk to induce arrhythmias by themselves. It was speculated that I(Ks) channel blockers may be free of this unwanted effect and several companies put effort to find compounds selective for this novel target. The strategies to find potent and selective I(Ks) channel will be reviewed as well as their first results in in-vitro and in-vivo models of arrhythmia. As side effects are a potential danger for this ubiquitous channel, also the safety studies with these compounds will be summarized.

Bone changes due to glucocorticoid application in an ovariectomized animal model for fracture treatment in osteoporosis.

In a pilot experiment comparing four different modalities for inducing osteoporosis in the sheep, a combination of ovariectomy, calcium/vitamin D-restricted diet and steroid administration was found to generate the highest decrease in bone mineral density (BMD). The aim of the present study was to quantify the outcome of this triple treatment in an animal model of osteoporosis in terms of alteration in bone mass, bone structure and bone mechanics. A total of 32 sheep were divided into two equal groups. Group 1 (age 3-5 years) was used as a normal control. Group 2 (age 7-9 years) was ovariectomized, fed a calcium/vitamin D-restricted diet and injected with methylprednisolone (MP) over 7 months (22 weeks MP solution, 6 weeks MP suspension). The BMD at the distal radius and tibia was determined preoperatively and at repeated intervals bilaterally using quantitative computed tomography. Steroid blood levels were determined 4 and 24 h after selected injections. BMD was measured at L3 and L4 after 7 months. Biopsies were taken from iliac crests, vertebral bodies and femoral heads, and bone structure parameters investigated by three-dimensional micro-CT. Compressive mechanical properties of cancellous bone were determined from biopsies of vertebral bodies and femoral heads. After 7 months of osteoporosis induction the BMD of cancellous bone decreased 36 +/- 3% in the radius and 39 +/- 4% in the tibia. Steroid blood levels 24 h after injection of MP suspension were significantly higher than after injection of MP solution. Changes in structural parameters of cancellous bone from the iliac crest, lumbar spine and femoral head in group 2 indicated osteoporosis-associated changes. In group 2 there was a significant reduction in BMD of the lumbar spine and a significant reduction in stiffness and failure load in compression testing of biopsies of lumbar vertebrae. In sheep, changes in the structural parameters of bone such as trabecular number and separation during osteoporosis induction are comparable to the human situation. The sheep model presented seems to meet the criteria for an osteoporosis model for fracture treatment with respect to mechanical and morphometric bone properties.

The role of KCNQ1/KCNE1 K(+) channels in intestine and pancreas: lessons from the KCNE1 knockout mouse.

KCNE1 (IsK, minK) co-assembles with KCNQ1 (KvLQT1) to form voltage-dependent K(+) channels. Both KCNQ1 and KCNE1 are expressed in epithelial cells of gut and exocrine pancreas. We examined the role of KCNQ1/KCNE1 in Cl(-) secretion in small and large intestine and exocrine pancreas using the KCNE1 knockout mouse. Immunofluorescence revealed a similar basolateral localization of KCNQ1 in jejunum and colon of KCNE1 wild-type and knockout mice. Electrogenic Cl(-) secretion in the colon was not affected by gene disruption of KCNE1; in jejunum forskolin-induced short-circuit current was some 40% smaller but without being significantly different. Inhibition of KCNQ1 channels by 293B (IC(50) 1 micromol l(-1)) and by IKS224 (IC(50) 14 nmol l(-1)) strongly diminished intestinal Cl(-) secretion. In exocrine pancreas of wild-type mice, KCNQ1 was predominantly located at the basolateral membrane. In KCNE1 knockout mice, however, the basolateral staining was less pronounced and the distribution of secretory granules was irregular. A slowly activating and 293B-sensitive K(+) current was activated via cholinergic stimulation in pancreatic acinar cells of wild-type mice. In KCNE1 knockout mice this K(+) current was strongly reduced. In conclusion intestinal Cl(-) secretion is independent from KCNE1 but requires KCNQ1. In mouse pancreatic acini KCNQ1 probably co-assembled with KCNE1 leads to a voltage-dependent K(+) current that might be of importance for electrolyte and enzyme secretion.

Properties and function of KCNQ1 K+ channels isolated from the rectal gland of Squalus acanthias.

KCNQ1 (KVLQT1) K+ channels play an important role during electrolyte secretion in airways and colon. KCNQ1 was cloned recently from NaCl-secreting shark rectal glands. Here we study the properties and regulation of the cloned sKVLQT1 expressed in Xenopus oocytes and Chinese hamster ovary (CHO) cells and compare the results with those obtained from in vitro perfused rectal gland tubules (RGT). The expression of sKCNQ1 induced voltage-dependent, delayed activated K+ currents, which were augmented by an increase in intracellular cAMP and Ca2+. The chromanol derivatives 293B and 526B potently inhibited sKCNQ1 expressed in oocytes and CHO cells, but had little effect on RGT electrolyte transport. Short-circuit currents in RGT were activated by alkalinization and were decreased by acidification. In CHO cells an alkaline pH activated and an acidic pH inhibited 293B-sensitive KCNQ1 currents. Noise analysis of the cell-attached basolateral membrane of RGT indicated the presence of low-conductance (<3 pS) K+ channels, in parallel with other K+ channels. sKCNQ1 generated similar small-conductance K+ channels upon expression in CHO cells and Xenopus oocytes. The results suggest the presence of low-conductance KCNQ1 K+ channels in RGT, which are probably regulated by changes in intracellular cAMP, Ca2+ and pH.

Synthesis and activity of novel and selective I(Ks)-channel blockers.

Since the discovery of the I(Ks)-potassium channel as the slowly activating component of the delayed rectifier current (I(k)) in cardiac tissue, the search for blockers of this current has been intense. During the screening of K(ATP)-channel openers of the chromanol type we found that chromanol 293B was able to block I(Ks). Chromanol 293B is a sulfonamide analogue of the K(ATP)-channel openers but had no activity on this target. Experiments were initiated to improve the activity and properties based on this lead compound. As a screening model we used Xenopus oocytes injected with human minK (KCNE1). Variations of the aromatic substituent and the sulfonamide group were prepared, and their activity was evaluated. We found that the greatest influence on activity was found in the aromatic substituents. The most active compounds were alkoxy substituted. We chose HMR1556 ((3R, 4S)-(+)-N-[-3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-N-methyl-ethanesulfonamide) 10a for development as an antiarrhythmic drug. The absolute configuration, resulting from an X-ray single-crystal structure analysis, was determined.