Successful long-term systemic sclerosis treatment by high-frequent low-dose B cell-depleting therapy.

OBJECTIVES: Systemic sclerosis (SSc) is a multiorgan disease with a 10-year mortality rate of up to 50 %. B cell-depleting therapy with rituximab (RTX) appears effective in SSc treatment, but data from randomized controlled trials (RCTs) are lacking, and the frequency and dosage of RTX in SSc have no consensus. We aimed to evaluate the long-term efficacy and safety of quarterly RTX administration in SSc. METHODS: This study retrospectively analyzed 40 patients with SSC treated with RTX twice within 14 days every 3 months from 2010 to 2020. The patients fulfilled the LeRoy and the American College of Rheumatology/European League Against Rheumatism Criteria for SSc. Modified Rodnan skin score (mRSS), lung function test results, and serum immunoglobulin (IgG, IgA, and IgM) concentrations were analyzed. RESULTS: A total of 40 patients with SSc received RTX over a median time of 3.9 years (range: 1-10 years). The median mRSS (baseline: 19, 24 months: 16, p < 0.001) demonstrated a significant improvement, and the predicted forced vital capacity was stable. No new or unexpected safety signals, especially regarding treatment-related infectious adverse events, were observed. Immunoglobulin concentrations were within normal range, and specific antibodies to pneumococcal polysaccharides were preserved despite long-term B cell-depleting therapy. None of the patients died during the observation period of up to 10 years. CONCLUSION: SSc was effectively and safely treated with low-dose RTX quarterly. RCTs are warranted to validate the advantage of continuous B cell depletion by quarterly low-dose RTX administration compared to other treatment intervals.

[IL-1-blockade with Anakinra during pregnancy : Retrospective analysis of efficacy and safety in female patients with familial Mediterranean fever]. / IL-1-Blockade mit Anakinra in der Schwangerschaft : Retrospektive Wirksamkeits- und Sicherheitsanalyse bei Patientinnen mit familiärem Mittelmeerfieber.

OBJECTIVE: To retrospectively assess and analyze the clinical efficacy and safety of off-label interleukin-1 (IL-1) blockade with anakinra during pregnancy of patients with familial Mediterranean fever (FMF). METHODS: Retrospective analysis of clinical and laboratory parameters making use of an electronic database system. Detailed descriptions of the genotype and phenotype of FMF are given and the course of the pregnancy and fetal development are reported. RESULTS: The data of three patients and a total of four pregnancies under treatedment with anakinra were analyzed. All patients were of Mediterranean origin, fulfilled the Tel Hashomer criteria for diagnosis of FMF and had a confirmed mutation in the MEFV gene. In all patients, treatment with anakinra was initiated due to an insufficient treatment response to colchicine. Anakinra led to a rapid response in all patients. In three pregnancies anakinra treatment was continued during the whole pregnancy, while in one pregnancy anakinra was started in the second trimester because of uncontrolled FMF activity. Fetal development was normal in all pregnancies. In two patients the fetuses were carried to term, while in one patient a primary cesarean section was carried out in week 33 because of an increased risk for complications. All children showed an unremarkable early childhood development without any signs of an existing disease. CONCLUSION: The data of our retrospective analysis suggest that IL-1-blockade by anakinra is an effective and safe treatment in pregnant women suffering from FMF, which can reliably prevent disease flares. In the four pregnancies presented the use of anakinra did not result in impaired fetal and (early) childhood development.

[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.

Feasibility of Perineal Defect Reconstruction with Simplified Fasciocutaneous Inferior Gluteal Artery Perforator (IGAP) Flaps after Tumor Resection of the Lower Rectum: Incidence and Outcome in an Interdisciplinary Approach.

BACKGROUND: Extralevator abdominoperineal excision (ELAPE) is a relatively new surgical technique for low rectal cancers, enabling a more radical approach than conventional abdominoperineal excision (APE) with a potentially better oncological outcome. To date, no standard exists for reconstruction after extended or extralevator approaches of abdominoperineal (ELAPE) resection for lower gastrointestinal cancer or inflammatory tumors. In the recent literature, techniques with myocutaneous flaps, such as the VY gluteal flap, the pedicled gracilis flap, or the pedicled rectus abdominis flaps (VRAM) are primarily described. We propose a tailored concept with the use of bilateral adipo-fasciocutaneous inferior gluteal artery perforator (IGAP) advancement flaps in VY fashion after ELAPE surgery procedures. This retrospective cohort study analyzes the feasibility of this concept and is, to our knowledge, one of the largest published series of IGAP flaps in the context of primary closure after ELAPE procedures. METHODS: In a retrospective cohort analysis, we evaluated all the consecutive patients with rectal resections from Jan 2017 to Sep 2021. All the patients with abdominoperineal resection were included in the study evaluation. The primary endpoint of the study was the proportion of plastic reconstruction and inpatient discharge. RESULTS: Out of a total of 560 patients with rectal resections, 101 consecutive patients with ELAPE met the inclusion criteria and were included in the study evaluation. The primary direct defect closure was performed in 72 patients (71.3%). In 29 patients (28.7%), the defect was closed with primary unilateral or bilateral IGAP flaps in VY fashion. The patients' mean age was 59.4 years with a range of 25-85 years. In 84 patients, the indication of the operation was lower rectal cancer or anal cancer recurrence, and non-oncological resections were performed in 17 patients. Surgery was performed in a minimally invasive abdominal approach in combination with open perineal extralevatoric abdominoperineal resection (ELAPE) and immediate IGAP flap reconstruction. The rate of perineal early complications after plastic reconstruction was 19.0%, which needed local revision due to local infection. All these interventions were conducted under general anesthesia (Clavien-Dindo IIIb). The mean length of the hospital stay was 14.4 days after ELAPE, ranging from 3 to 53 days. CONCLUSIONS: Since radical resection with a broad margin is the standard choice in primary, sphincter-infiltrating rectal cancer and recurrent anal cancer surgery in combination with ELAPE, the choice technique for pelvic floor reconstruction is under debate and there is no consensus. Using IGAP flaps is a reliable, technical, easy, and safe option, especially in wider defects on the pelvic floor with minimal donor site morbidity and an acceptable complication (no flap necrosis) rate. The data for hernia incidence in the long term are not known.

Transcriptional landscapes of floral meristems in barley.

Organ development in plants predominantly occurs postembryonically through combinatorial activity of meristems; therefore, meristem and organ fate are intimately connected. Inflorescence morphogenesis in grasses (Poaceae) is complex and relies on a specialized floral meristem, called spikelet meristem, that gives rise to all other floral organs and ultimately the grain. The fate of the spikelet determines reproductive success and contributes toward yield-related traits in cereal crops. Here, we examined the transcriptional landscapes of floral meristems in the temperate crop barley (Hordeum vulgare L.) using RNA-seq of laser capture microdissected tissues from immature, developing floral structures. Our unbiased, high-resolution approach revealed fundamental regulatory networks, previously unknown pathways, and key regulators of barley floral fate and will equally be indispensable for comparative transcriptional studies of grass meristems.

Convergent evolution of pain-inducing defensive venom components in spitting cobras.

Convergent evolution provides insights into the selective drivers underlying evolutionary change. Snake venoms, with a direct genetic basis and clearly defined functional phenotype, provide a model system for exploring the repeated evolution of adaptations. While snakes use venom primarily for predation, and venom composition often reflects diet specificity, three lineages of cobras have independently evolved the ability to spit venom at adversaries. Using gene, protein, and functional analyses, we show that the three spitting lineages possess venoms characterized by an up-regulation of phospholipase A2 (PLA2) toxins, which potentiate the action of preexisting venom cytotoxins to activate mammalian sensory neurons and cause enhanced pain. These repeated independent changes provide a fascinating example of convergent evolution across multiple phenotypic levels driven by selection for defense.

Home-based subcutaneous immunoglobulin G replacement therapy under real-life conditions in children and adults with antibody deficiency.

BACKGROUND: Subcutaneous immunoglobulin (SCIG) therapy is an alternative to intravenous immunoglobulin (IVIG) therapy. METHODS: We evaluated the efficacy and safety of the SCIG Vivaglobin(formerly known as Beriglobin SC) under real-life conditions in a post-marketing observational study in 82 patients with primary or secondary antibody deficiencies. Health-related quality of life (HRQoL) was evaluated in a subset of 30 patients previously treated with IVIG (including 11 children <14 years) using the Short Form 36 (SF-36) for patients > or = 14 years of age (adults) and the Child Health Questionnaire - Parental Form 50 (CHQ-PF50) for children <14 years of age. Treatment preferences were assessed in adults. RESULTS: The mean serum immunoglobulin G (IgG) trough level during SCIG treatment (7.5 g/L) was higher than during previous IVIG treatment (6.6 g/L; p<0.01). The investigators assessed the efficacy of SCIG therapy as "excellent" in 89% of patients. No systemic adverse drug reactions were observed. Improvements by > or = 5 points were observed in 5 of 8 SF-36 subscales and in 6 of 12 CHQ-PF50 subscales. Statistically significant improvements (p< or =0.05) were observed for the SF-36 subscales of bodily pain, general health perceptions, and vitality (adults), and for the CHQ-PF50 subscales of general health perceptions, parental impact - time, parental impact - emotional, and family activities (children). Patients preferred SCIG over IVIG therapy (92%) and home therapy over therapy at the clinic/physician (83%). CONCLUSION: This study confirms that therapy with Vivaglobin at home is effective, safe, well tolerated, and improves quality of life in patients with antibody deficiency.

An in vivo demonstration of efficacy and acute safety of burst wave lithotripsy using a porcine model.

Burst wave lithotripsy (BWL) is a new non-invasive method for stone comminution using bursts of sub-megahertz ultrasound. A porcine model of urolithiasis and techniques to implement BWL treatment has been developed to evaluate its effectiveness and acute safety. Six human calcium oxalate monohydrate stones (6-7 mm) were hydrated, weighed, and surgically implanted into the kidneys of three pigs. Transcutaneous stone treatments were performed with a BWL transducer coupled to the skin via an external water bath. Stone targeting and treatment monitoring were performed with a co-aligned ultrasound imaging probe. Treatment exposures were applied in three 10-minute intervals for each stone. If sustained cavitation in the parenchyma was observed by ultrasound imaging feedback, treatment was paused and the pressure amplitude was decreased for the remaining time. Peak negative focal pressures between 6.5 and 7 MPa were applied for all treatments. After treatment, stone fragments were removed from the kidneys. At least 50% of each stone was reduced to <2 mm fragments. 100% of four stones were reduced to <4 mm fragments. Magnetic resonance imaging showed minimal injury to the functional renal volume. This study demonstrated that BWL could be used to effectively fragment kidney stones with minimal injury.

Phase II intensive monitored cardiac rehabilitation for coronary artery disease and coronary risk factors--a six-session protocol.

To evaluate phase II intensive monitored cardiac rehabilitation using a 6-level, 6-session protocol, 31 patients were placed in a progressive 6-level exercise protocol with careful supervision and assessment of heart rate, rhythm, blood pressure and perceived exertion. Duration after the cardiac event ranged from 12 days to 8 years (median 10 months). Each exercise prescription was based on exercise testing with oxygen consumption determinations. Exercise activities were individually prescribed according to percentages of maximal MET level achieved on the exercise test. Each exercise session incorporated calisthenics, treadmill exercise, and bicycle and arm ergometry with progressively greater workloads on the various stations. All patients completed the 6 levels within 6 sessions of approximately 1 hour each, and achieved their designated 50 to 75% target heart rate with perceived exertion level 13 or less. There were no critical cardiac events, i.e., high-grade ventricular arrhythmias or myocardial infarction. All completed the 6-level protocol and progressed to a nonmonitored exercise program with no difficulty. The results of this short-term method of telemetry-monitored rehabilitation suggest benefits of proper exercise instruction, successful achievement of the 50 to 75% exercise target heart rate, detection of minor new arrhythmias and alterations of blood pressure response, adequate use of the perceived exertion scale, and a safe and effective transition to subsequent exercise programs.

Telephonically-monitored home exercise early after coronary artery bypass surgery.

To evaluate the usefulness of telephonically-monitored home exercise in patients within two weeks postcoronary bypass surgery, we randomly enrolled 46 male patients in a 12-week home program of either short walks or bicycle ergometry. Home exercise was done five times weekly and monitored both before and immediately after three times weekly. New arrhythmias or conduction disturbances were detected in 18 of 23 (78 percent) of the bicycle group and in 20 of 23 (87 percent) of the short walk patients. New symptoms developed in three patients, two from the short walk group and one from the bicycle group. Two bikers and one walker developed elevated blood pressure; all were referred to physicians and were successfully managed. Electrocardiographic abnormalities led directly to diagnostic and therapeutic intervention in nine of the 46 patients-four bikers and five walkers. There were no complications such as ventricular tachycardia or ventricular fibrillation. Technically clear telephone rhythm strips were obtained from patients calling both locally and long distance.

Analyzing the red-shift characteristics of azulenic, naphthyl, other ring-fused and retinyl pigment analogs of bacteriorhodopsin.

Prompted by the near infrared-absorbing properties of some of the azulenic bacteriorhodopsin (bR) analogs, we have analyzed their absorption characteristics along with 11 new related ring-fused analogs and the corresponding Schiff bases (SB) and protonated Schiff bases (PSB). The following three factors are believed to contribute to the total red shift of each of the pigment analogs (sigma RS): perturbation of the basic chromophore (SB shift, delta SB), protonation of the SB (PSB shift, PSBS) and protein perturbation (the opsin shift, OS). For each factor, effects of structural modifications were examined. For the red-shifted pigments, percent OS has been suggested as an alternate way of measuring protein perturbation. Computer-simulated chromophores provided evidence against any explanation involving altered shapes of the binding pocket as a major cause for absorption differences. Implications of the current bR results on preparation of further red-shifted bR and possible application to visual pigment analogs are discussed.

Teaching and assessing communication skills in Maastricht: the first twenty years.

In order to share the issues involved in setting up a communication skills training programme in a medical school, the development of such a programme at the Skillslab of Maastricht Medical School, the Netherlands, is described and the problems encountered are addressed. A multidisciplinary working group developed teaching goals for communication skills, focused on observable behaviour to be displayed by students. These teaching goals were incorporated in a generic model for doctor-patient communication. A longitudinal training programme was created, throughout the four years of the preclinical curriculum. Students meet in small groups of 10, once every 2 weeks. In between group sessions they practise consultation skills in simulated patient contacts. Communication skills are assessed in the annual multiple station examination. In the development of this programme the following consecutive actions were taken: teaching material was produced, and an assessment tool was developed, as were instruments for programme evaluation. The programme evaluation allowed student feedback to teachers, the teachers' departments, and the administration of the medical school. Finally, teacher training was professionalized.

[Changes of cognitive brain functions in the elderly by Kneipp therapy]. / Veränderung kognitiver Hirnleistungen im Alter Durch Kneipp-Anwendungen.

INTRODUCTION: Pharmacological and nonpharmacological treatment of brain syndrome is multifarious. Until now, plain external applications of physical stimuli, as used daily in geriatric care, were not explored regarding their influence on cognitive brain function. The aim of this randomized cross-over study was to examine the influence of dermatoreceptive stimuli on cognitive brain function of healty geriatric volunteers. METHODS: 24 healthy volunteers (23 women, 1 man) were randomized into 2 groups (cross-over design). Group A (mean age +/- SD: 68.8 +/- 6.2 years) was treated according to the following regime: at first a 10-12 degrees C cold stimulus for 10 s (a so-called Kneipp face shower) and afterwards a cold wet pack of 10-12 degrees C at the neck for 1 min. Group B (age 69.8 +/- 5.3 years) was subjected to an identical procedure but with warm thermoindifferent temperatures of 34-36 degrees C. After 1 week the two groups were interchanged. The parameters of interest were the critical flicker frequency (CFF) and the latencies of the event-related P300 potentials of the visually evoked potentials (VEP), which can be considered the electroencephalographic substrate of the cognitive functional ability. The CFFs and the P300 latencies and amplitudes were measured directly before and 10 min after the application of the above-mentioned stimuli. Furthermore, the CFFs were recorded a second and third time 30 and 60 min later. RESULTS: Following application of cold-water stimuli, the CFF increased from (mean +/- SE) 32.55 +/- 0.44 s(-1) to 33.06 +/- 0.44 s(-1) (p = 0.003) 10 min after the stimulus. 30 min later the CFF was still elevated at 32.95 +/- 0.47 s(-1) (p = 0.043). The P300 latencies decreased by 4.8% (p < 0.001) after cold-water application from 266.5 +/- 5.28 to 253.7 +/- 4.22 ms. After warm stimuli they increased from 258.69 +/- 3.71 to 266.17 +/- 5.03 ms (p = 0.01). The P300 amplitudes were elevated by 5% only with the cold stimuli (p = 0.004). CONCLUSION: Cold water applied locally to face and neck region is able to provoke significant improvements of cognitive abilities.

[Changes in the form of the interosseous hood during extension and flexion of the metacarpophalangeal joint]. / Formänderungen der Sehnenhaube bei Streckung und Beugung des Metakarpophalangealgelenkes.

Finger flexion initiated at the distal and proximal interphalangeal joint level forces the extensor tendon to move distally. Therefore, the interosseous hood fixed to the extensor apparatus moves distally, too. The proximal part of the hood which is located at the level of the metacarpal head during extension of the finger slides distally along the basis of the proximal phalanx. Due to the much smaller cross-section of the phalanx compared to the metacarpal head, the palmar border of the interosseous hood is shifted palmarly. This produces a two-fold effect concerning the metacarpophalangeal joint. First, it leads to an increasing flexion moment of the intrinsic muscles during flexion of the metacarpophalangeal joint. Second, the same mechanism improves the ability of abduction and adduction in the metacarpophalangeal joint during extension of the finger. In this position, the proximal part of the interosseous hood covers the metacarpal head and the strong palmar bundles of the hood are pushed to the ulnar and radial sides resulting in a greater distance to the abduction/adduction axis of the MP-joint. The other effect concerns the proximal interphalangeal joint. The described transformation of the interosseous hood during flexion especially of its proximal part causes a curved deformation of the strong palmar border of the interosseous hood. The power of the intrinsic muscles inserting at the interosseous hood is passed along this smooth curve on its way to the dorsal side of the proximal interphalangeal joint thus allowing a continuous extension of the proximal interphalangeal joint in all flexion phases of the MP-joint. The typical transformation of the interosseous hood is regulated by the form of the underlying bone and ligament apparatus and can be understood as a passive mechanism effecting in a senseful change of muscle function as the active element during finger flexion and extension. These not yet described morphological data concerning the transformation of the interosseous hood during finger flexion and the functional interpretation complete the former described mechanism of flexion by Landsmeer (1955) and Landsmeer and Long (1965).