Transitional changes in the structure of C-reactive protein create highly pro-inflammatory molecules: Therapeutic implications for cardiovascular diseases.

C-reactive protein (CRP) is the prototypic acute-phase reactant that has long been recognized almost exclusively as a marker of inflammation and predictor of cardiovascular risk. However, accumulating evidence indicates that CRP is also a direct pathogenic pro-inflammatory mediator in atherosclerosis and cardiovascular diseases. The 'CRP system' consists of at least two protein conformations with distinct pathophysiological functions. The binding of the native, pentameric CRP (pCRP) to activated cell membranes leads to a conformational change resulting in two highly pro-inflammatory isoforms, pCRP* and monomeric CRP (mCRP). The deposition of these pro-inflammatory isoforms has been shown to aggravate the localized tissue injury in a broad range of pathological conditions including atherosclerosis and thrombosis, myocardial infarction, and stroke. Here, we review recent findings on how these structural changes contribute to the inflammatory response and discuss the transitional changes in the structure of CRP as a novel therapeutic target in cardiovascular diseases and overshooting inflammation.

Evaluation of the Suprafascial Thin ALT Flap in Foot and Ankle Reconstruction.

BACKGROUND: Distal lower extremity reconstruction can be challenging in terms of flap design. Bulky flaps result in limited mobility accompanied with the need of customized footwear. Raising the ALT-flap in a superficial fascial plane (thin ALT-flap) can be beneficial. This study evaluates thin ALT-flaps for lower distal extremity reconstruction. METHODS: In a retrospective study, patients that underwent microvascular extremity reconstruction at the level of the ankle and dorsal foot at the University of Freiburg from 2008-2018 were reviewed. RESULTS: 95 patients could be included in the study (35 perforator flaps, 8 fascia flaps and 54 muscle flaps).Among the perforator flaps, 21 ALT-flaps were elevated conventionally and 14 in the superficial fascial plane (thin ALT-flap). Among the conventional ALT-flaps, there was one flap loss (5%) and one successful revision (5%). 5(24%) flaps received secondary thinning. 57%(n = 12) were able to wear conventional footwear. There were 2(15%) successful revisions of thin ALT-flaps. 100% of thin ALT-flaps survived and 85%(n = 11) of the patients wore ordinary footwear after defect coverage.Among fascial flaps, 50%(n = 4) had to be revised with 2(25%) complete and 1 (13%) partial flap loss. All patients achieved mobility in ordinary shoes (n = 8).In muscle flaps, there were 7(13%) revisions and 5(9%) flap losses. 5(9%) flaps received secondary thinning. Only 33%(n = 18) were mobile in ordinary footwear. CONCLUSION: The thin ALT-flap is a save one-stage evolution for lower distal extremity reconstruction with a favorable flap survival rate. Compared with conventional ALT-flaps it might be beneficial in reducing the need for expensive custom fitted shoes and secondary thinning procedures.

BNST and amygdala activation to threat: Effects of temporal predictability and threat mode.

Recent animal and human studies highlight the uncertainty about the onset of an aversive event as a crucial factor for the involvement of the centromedial amygdala (CM) and bed nucleus of the stria terminalis (BNST) activity. However, studies investigating temporally predictable or unpredictable threat anticipation and confrontation processes are rare. Furthermore, the few existing fMRI studies analyzing temporally predictable and unpredictable threat processes used small sample sizes or limited fMRI paradigms. Therefore, we measured functional brain activity in 109 predominantly female healthy participants during a temporally predictable-unpredictable threat paradigm, which aimed to solve limited aspects of recent studies. Results showed higher BNST activity compared to the CM during the cue indicating that the upcoming confrontation is aversive relative to the cue indicating an upcoming neutral confrontation. Both the CM and BNST showed higher activity during the confrontation with unpredictable and aversive stimuli, but the reaction to aversive confrontation relative to neutral confrontation was stronger in the CM compared to the BNST. Additional modulation analyses by NPSR1 rs324981 genotype revealed higher BNST activity relative to the CM in unpredictable anticipation relative to predictable anticipation in T-carriers compared to AA carriers. Our results indicate that during the confrontation with aversive or neutral stimuli, temporal unpredictability modulates CM and BNST activity. Further, there is a differential activity concerning threat processing, as BNST is more involved when focussing on fear-related anticipation processes and CM is more involved when focussing on threat confrontation.

Targeting C-Reactive Protein in Inflammatory Disease by Preventing Conformational Changes.

C-reactive protein (CRP) is a pentraxin that has long been employed as a marker of inflammation in clinical practice. Recent findings brought up the idea of CRP to be not only a systemic marker but also a mediator of inflammation. New studies focused on structural changes of the plasma protein, revealing the existence of two distinct protein conformations associated with opposed inflammatory properties. Native, pentameric CRP (pCRP) is considered to be the circulating precursor form of monomeric CRP (mCRP) that has been identified to be strongly proinflammatory. Recently, a dissociation mechanism of pCRP has been identified on activated platelets and activated/apoptotic cells associated with the amplification of the proinflammatory potential. Correspondingly, CRP deposits found in inflamed tissues have been identified to exhibit the monomeric conformation by using conformation-specific antibodies. Here we review the current literature on the causal role of the dissociation mechanism of pCRP and the genesis of mCRP for the amplification of the proinflammatory potential in inflammatory reactions such as atherosclerosis and ischemia/reperfusion injury. The chance to prevent the formation of proinflammatory mediators in ubiquitous inflammatory cascades has pushed therapeutic strategies by targeting pCRP dissociation in inflammation. In this respect, the development of clinically applicable derivatives of the palindromic compound 1,6-bis(phosphocholine)-hexane (1,6-bis PC) should be a major focus of future CRP research.

[Sleep-disordered breathing in patients with chronic heart failure: epiphenomenon or bidirectional relationship]. / Schlafbezogene Atmungsstörungen bei Patienten mit Herzinsuffizienz: Epiphänomen oder wechselseitige Krankheitsbeeinflussung.

Sleep-disordered breathing (SDB) constitutes a highly prevalent comorbidity in patients with chronic heart failure (HF, approximately 45%). Both diseases are related in a bidirectional way: Obstructive sleep apnoea (OSA) can contribute to the development of HF via multiple mechanisms. Apnoea-related acute rise of cardiac afterload as well as manifest hypertension may contribute to the development of myocardial hypertrophy and thus HF. In addition, OSA increases the risk for myocardial infarction and impaired recovery of cardiac function after the event. Impaired cardiac function itself may contribute to the development of obstructive and central sleep apnoea (SA). Therefore, optimal medical management of HF is part of the therapy of SDB in such patients. Treatment of SDB with different modes of positive airway pressure suppresses apnoeas and hypopnoeas, improves sleep and may improve related symptoms and cardiac function of affected patients. Considering the high coincidence of SDB and HF, the adequate diagnosis of SDB and evaluation of indication for therapy of SDB performed in a specialised centre is advised.

Variability of the lateral femoral cutaneous nerve: An anatomic basis for planning safe surgical approaches.

Current surgical assumptions identify the lateral femoral cutaneous nerve (LFCN) running just under the inguinal ligament two fingerbreadths medial to the anterior superior iliac spine (ASIS). On the basis of the increasing incidence of Meralgia Paresthetica associated with various surgical procedures, it is clear that surgeons are relying on an inadequate description of the nerve's course. This study provides a better understanding of the variability of the LFCN with regards to its relationship to the ASIS and the depth at which it passes deep to the inguinal ligament. A total of 35 bodies were examined yielding 65 sets of data. Dissections were performed on 26 formalin fixed cadavers and 9 fresh morgue specimens. Measurements and calculations were made with regard to the distance from the LFCN to the ASIS along the inguinal ligament, the depth of the LFCN as it crossed the inguinal ligament, and the length of the inguinal ligament. The LFCN was observed to cross the inguinal ligament 1.4 +/- 0.4 cm medial to the ASIS with a standard deviation of 1.5 cm. The LFCN traversed the inguinal ligament 1.0 +/- 0.1 cm deep to the ligament with a standard deviation of 0.6 cm. The LFCN runs approximately one fingerbreadth medial to the ASIS. The nerve may be found far more medial or lateral than expected with several distinct branching patterns. In addition, the LFCN crosses deeper to the inguinal ligament than previously described in the literature, with a high variability of depth between specimens.

Oropharyngeal administration of colostrum to extremely low birth weight infants: theoretical perspectives.

Studies in adults have shown that the oropharyngeal route can be used to effectively and safely administer interferon-alpha, an immune cell-derived cytokine, to patients who are unable to tolerate its parenteral administration. The mechanism for this appears to be the stimulatory effects of the cytokine, on the oropharyngeal-associated lymphoid tissue system. Own mother's colostrum (OMC) is rich in cytokines and other immune agents that provide bacteriostatic, bacteriocidal, antiviral, anti-inflammatory and immunomodulatory protection against infection. OMC may be especially protective for the extremely low birth weight (ELBW) infant in the first days of life; however clinical instability typically precludes enteral feedings during this period. Oropharyngeal administration is a potential alternative method of providing OMC. Oropharyngeal administration of OMC may have immunomodulatory effects on the recipient infant, and would be especially beneficial to the ELBW infant who would otherwise remain nil per os during the first days of life.

CGRP function-blocking antibodies inhibit neurogenic vasodilatation without affecting heart rate or arterial blood pressure in the rat.

BACKGROUND AND PURPOSE: Calcitonin gene-related peptide (CGRP) receptor antagonists effectively abort migraine headache and inhibit neurogenic vasodilatation in humans as well as rat models. Monoclonal antibodies typically have long half-lives, and we investigated whether or not function-blocking CGRP antibodies would inhibit neurogenic vasodilatation with a long duration of action and therefore be a possible approach to preventive therapy of migraine. During chronic treatment with anti-CGRP antibodies, we measured cardiovascular function, which might be a safety concern of CGRP inhibition. EXPERIMENTAL APPROACH: We used two rat blood flow models that measure electrically stimulated vasodilatation in the skin or in the middle meningeal artery (MMA). These vasomotor responses are largely dependent on the neurogenic release of CGRP from sensory afferents. To assess cardiovascular function during chronic systemic anti-CGRP antibody treatment, we measured heart rate and blood pressure in conscious rats. KEY RESULTS: Treatment with anti-CGRP antibodies inhibited skin vasodilatation or the increase in MMA diameter to a similar magnitude as treatment with CGRP receptor antagonists. Although CGRP antibody treatment had a slower onset of action than the CGRP receptor antagonists, the inhibition was still evident 1 week after dosing. Chronic treatment with anti-CGRP antibodies had no detectable effects on heart rate or blood pressure. CONCLUSIONS AND IMPLICATIONS: We showed for the first time that anti-CGRP antibodies exert a long lasting inhibition of neurogenic vasodilatation in two different rat models of arterial blood flow. We have provided strong preclinical evidence that anti-CGRP antibody may be a suitable drug candidate for the preventive treatment of migraine.

Myoclonus-dystonia: significance of large SGCE deletions.

Myoclonus-dystonia (M-D) is an autosomal-dominant movement disorder caused by mutations in SGCE. We investigated the frequency and type of SGCE mutations with emphasis on gene dosage alterations and explored the associated phenotypes. We tested 35 M-D index patients by multiplex ligation-dependent probe amplification (MLPA) and genomic sequencing. Mutations were found in 26% (9/35) of the cases, all but three with definite M-D. Two heterozygous deletions of the entire SGCE gene and flanking DNA and a heterozygous deletion of exon 2 only were detected, accounting for 33% (3/9) of the mutations found. Both large deletions contained COL1A2 and were additionally associated with joint problems. Further, we discovered one novel small deletion (c.771_772delAT, p.C258X) and four recurrent point mutations (c.289C>T, p.R97X; c.304C>T, p.R102X; c.709C>T, p.R237X; c.1114C>T, p.R372X). A Medline search identified 22 articles on SGCE mutational screening. Sixty-four unrelated M-D patients were described with 41 different mutations. No genotype-phenotype association was found, except in patients with deletions encompassing additional genes. In conclusion, a rigorous clinical preselection of patients and careful accounting for non-motor signs should precede mutational tests. Gene dosage studies should be included in routine SGCE genetic testing.

[Stroke: causes and classification]. / Schlaganfall: Ursachen und Klassifikation.

Cerebrovascular disease is caused by ischaemic stroke, intracerebral haemorrhage, subarachnoidal haemorrhage or cerebral vein and sinus thrombosis. Approximately 80% of all cerebrovascular accidents are caused by ischaemic stroke, whereas 20% are due to primary haemorrhage. This article summarizes the typical causes of each of the four main groups of cerebrovascular disease and points out clinical differences. Special attention is given to transitory ischemic attacks since new reports underline the necessity of early diagnostic and therapeutic intervention. Useful diagnostic and clinical scales are presented and discussed.

[Coagulation disorders and stroke]. / Gerinnungsstörungen und Schlaganfall.

Hereditary and acquired coagulation disorders may play an important role in the pathophysiology of acute ischaemic stroke. Because of the low prevalence of these disorders and the considerable costs of unmindful diagnostic effort, a custom-tailored approach is desirable. Suggestive in favour of a possible prothrombotic clotting disorder are young patients, repeated episodes of thrombosis in the patient's history, inappropriate atherosclerotic vascular changes, previous repeated miscarriages in stroke patients, or structural cardiac abnormalities as a patent foramen ovale. Disorders affecting antithrombin III, protein C und S, APC-resistance, the prothrombin mutation, homocysteinaemia, antiphospholipid antibodies, and procoagulatory cellular interaction are discussed.

[Therapy of acute stroke]. / Akuttherapie des Schlaganfalls.

Current therapeutic concepts for acute cerebral ischaemia and cerebral haemorrhage are summarized. Patient selection for thrombolysis, the role of stroke MRI and the choice of recanalization techniques are discussed. The treatment of intracerebral haemorrhage with particular emphasis on evacuation of haematoma and acute haemostatic therapy are discussed.

Association between benign and malignant peripheral nerve sheath tumors in NF1.

OBJECTIVE: People with neurofibromatosis type 1 (NF1) have a 10% lifetime risk of developing a malignant peripheral nerve sheath tumor (MPNST). MPNSTs are often metastatic and are a frequent cause of death among people with NF1. Clinical evidence suggests that most MPNSTs in people with NF1 develop from preexisting plexiform neurofibromas. However, it is not known whether an individual's risk of developing an MPNST is associated with the burden of benign neurofibromas. The authors conducted a study to determine whether people with NF1 who have benign neurofibromas of various kinds are at greater risk of developing MPNSTs than patients with NF1 who lack these benign tumors. METHODS: Clinical information on 476 NF1 probands in the Henri Mondor Database was analyzed by logistic regression to examine associations between MPNSTs and internal plexiform, superficial plexiform, subcutaneous, and cutaneous neurofibromas. RESULTS: Individuals with subcutaneous neurofibromas were approximately three times more likely to have internal plexiform neurofibromas or MPNSTs than individuals without subcutaneous neurofibromas. Individuals with internal plexiform neurofibromas were 20 times more likely to have MPNSTs than individuals without internal plexiform neurofibromas. When this analysis was done with both subcutaneous and internal plexiform neurofibromas as explanatory variables, only the association of MPNSTs with internal plexiform neurofibromas remained significant. CONCLUSIONS: The observation that malignant peripheral nerve sheath tumors are strongly associated with internal plexiform neurofibromas suggests that patients with neurofibromatosis type 1 with these benign tumors warrant increased surveillance for malignancy.

Symptoms associated with malignancy of peripheral nerve sheath tumours: a retrospective study of 69 patients with neurofibromatosis 1.

BACKGROUND: Neurofibromatosis 1 (NF1) is a common genetic disorder with variable clinical manifestations and an unpredictable course. Plexiform neurofibromas are common complications of NF1. Their malignant transformation is the main cause of mortality in adult patients with NF1. OBJECTIVES: To identify clinical factors associated with malignant transformation of plexiform neurofibromas. METHODS: Using the database of our neurofibromatosis clinic we included in a retrospective study all patients with NF1 having at least one peripheral nerve sheath tumour for which they underwent surgery or surgical biopsy. Predictive values for malignant transformation of three clinical symptoms, i.e. pain, enlargement of mass and neurological symptoms, were evaluated in association with histological parameters. RESULTS: Of 69 patients studied, 48 had at least one plexiform neurofibroma and 21 had a malignant peripheral nerve sheath tumour. Only enlargement of the tumour had high negative and positive predictive values for malignant transformation: 0.92 and 0.95, respectively. In multivariate analysis, tumour enlargement was independently associated with malignant transformation (odds ratio 167.8, 95% confidence interval 14.0-2012.1). CONCLUSIONS: From a practical point of view, pain, neurological deficit and enlargement of a pre-existing peripheral nerve sheath tumour in NF1 must lead to deep surgical biopsy to rule out malignant transformation.

Platelet activation and platelet-leucocyte interaction in patients with migraine. Subtype differences and influence of triptans.

As migraine is the result of an inflammatory mechanism with serotonergic signalling, leucocyte function, platelet function and intercellular communication between those cells is likely to be connected to the final pathway of the disease. We examined P-selectin expression on platelets (platelet activation) and leucocyte-platelet aggregate formation in 72 migraine patients during their attack-free interval and controls using a flow cytometric assay. Patients suffering from migraine without aura had a significantly increased platelet activation and leucocyte-platelet aggregation compared with the control group, unlike the migraine patients with aura. Patients who had taken a triptan within 3 days prior to the investigation showed platelet activation values similar to the control group. The variations in platelet activation patterns of migraine subgroups could indicate different pathomechanisms. Even outside an attack, migraine patients, particularly those without aura, show an increased level of platelet activation which seems to be down-regulated by triptans. This mechanism may account for the triptan-induced increases in headache frequency. The involvement of proinflammatory platelet-leucocyte cross-talk suggests a possible therapeutic strategy using anti-inflammatory drugs.

Platelet-leukocyte interaction and platelet activation in acute stroke with and without preceding infection.

OBJECTIVE: Acute coronary syndromes and ischemic cerebral stroke share similarities regarding elevated platelet activation. In coronary syndromes, the importance of inflammation with platelet-leukocyte interaction has been demonstrated. Recent infection is an established risk factor for ischemic stroke; the role of platelet-leukocyte interaction in these patients had not been investigated. METHODS AND RESULTS: Using a flow cytometric assay we investigated 58 stroke patients, 21 with and 37 without infection 1 week before acute cerebral ischemia, and compared them to 58 controls with regard to platelet-leukocyte aggregation and platelet activation on admission and on day 7. Patients with previous infection were significantly up-regulated with regard to platelet activation and platelet-leukocyte aggregation compared with patients without infection. On day 7, these increases in the postinfective group had drawn level with the lower values of the other patients. As reported previously, recent infection was associated with a more severe postischemic deficit. CONCLUSIONS: These results suggest an important role of intercellular platelet-leukocyte interaction in the pathophysiology of acute cerebral ischemia which may also contribute to the increased incidence and clinical severity of ischemic stroke following infection. This may lead to therapeutic considerations of blocking intercellular adhesion molecules like P-selectin or the P-selectin glycoprotein ligand.

Platelet-leukocyte interaction and platelet activation in migraine: a link to ischemic stroke?

OBJECTIVES: Migraine has been identified as an independent risk factor for ischemic stroke. Both neurogenic inflammation and platelet activation have been linked to the pathophysiology of migraine. Increased platelet activation results in up-regulation of specific binding to leukocytes which promotes pro-inflammatory leukocyte secretion and their tethering to endothelium, a mechanism that has been demonstrated in stroke and which could provide a link to migraine. We aimed to determine whether platelet-leukocyte aggregation is increased in migraine patients outside an acute attack. METHODS: Seventy two patients with migraine according to IHS criteria were compared to a control group (n = 72). Whole blood flow cytometry was used to quantify the activation dependent P selectin on the platelet, and to assess the fraction of platelets bound to the different leukocyte subsets. RESULTS: Migraine patients showed significantly more platelet-leukocyte aggregates compared to the control subjects (p = 0.003). This effect was driven by an increased polymorphonuclear cell-platelet aggregation (p = 0.003) whereas platelet aggregation with monocytes and lymphocytes was not. Platelet activation was also increased (p = 0.001). CONCLUSIONS: In migraine pro-inflammatory platelet adhesion to leukocytes occurs during the headache free interval similar to that seen in acute coronary and cerebrovascular syndromes. This may suggest a link between migraine and stroke on a cellular level.