Serum autoantibody reactivity in bullous pemphigoid is associated with neuropsychiatric disorders and the use of antidiabetics and antipsychotics: a large, prospective cohort study.

BACKGROUND: Bullous pemphigoid (BP), the by far most frequent autoimmune blistering skin disease (AIBD), is immunopathologically characterized by autoantibodies against the two hemidesmosomal proteins BP180 (collagen type XVII) and BP230 (BPAG1 or dystonin). Several comorbidities and potentially disease-inducing medication have been described in BP, yet a systematic analysis of these clinically relevant findings and autoantibody reactivities has not been performed. OBJECTIVE: To determine associations of autoantibody reactivities with comorbidities and concomitant medication. METHODS: In this prospective multicenter study, 499 patients diagnosed with BP in 16 European referral centers were included. The relation between anti-BP180 NC16A and anti-BP230 IgG ELISA values at the time of diagnosis as well as comorbidities and concomitant medication collected by a standardized form were analysed. RESULTS: An association between higher serum anti-BP180 reactivity and neuropsychiatric but not atopic and metabolic disorders was observed as well as with the use of insulin or antipsychotics but not with dipeptidyl peptidase-4 (DPP4) inhibitors, inhibitors of platelet aggregation and L-thyroxine. The use of DPP4 inhibitors was associated with less anti-BP180 and anti-BP230 reactivity compared with BP patients without these drugs. This finding was even more pronounced when compared with diabetic BP patients without DPP4 inhibitors. Associations between anti-BP180 and anti-BP230 reactivities were also found in patients using insulin and antipsychotics, respectively, compared with patients without this medication, but not for the use of inhibitors of platelet aggregation, and L-thyroxine. CONCLUSION: Taken together, these data imply a relation between autoantibody reactivities at the time of diagnosis and both neuropsychiatric comorbidities as well as distinct concomitant medication suggesting a link between the pathological immune mechanisms and clinical conditions that precede the clinically overt AIBD.

MINIMALLY INVASIVE TREATMENT OF IDIOPATHIC SYRINGOMYELIA USING MYRINGOTOMY T-TUBES: A CASE REPORT AND TECHNICAL NOTE.

Syringomyelia is characterized by a fluid-filled cavity within the spinal cord. Expansion of the syrinx often results in the clinical course of progressive neurologic deficit. Surgery for syringomyelia generally aims to treat the underlying cause, if it is known. However, little is known about idiopathic syringomyelia, which requires specific management. In our paper, an alternative, minimally invasive treatment option for large symptomatic idiopathic cervicothoracic syrinx is described and discussed. We present a case of a 44-year-old male without a history of spinal cord trauma, infection, or other pathologic processes, who presented for thoracic pain. Due to progressive pain and left leg paresis, magnetic resonance imaging (MRI) was performed and revealed extensive septated syringomyelia from T5 to T7 and hydromyelia cranially. We applied minimally invasive technique for shunting the idiopathic syrinx into the subarachnoid space using two Richards modified myringotomy T-tubes. Postoperative MRI revealed significant decrease in the syrinx size and clinical six-month follow-up showed improvement of clinical symptoms. This minimally invasive treatment of syringomyelia was found to be an effective method for idiopathic septated syrinx, without evident underlying cause. However, long-term follow-up and more patients are necessary for definitive evaluation of this technique.

Schnitzler syndrome.

Schnitzler syndrome is a very rare acquired systemic disease with many similarities to hereditary autoinflammatory syndromes. The main characteristics are generalized exanthema and IgM monoclonal gammopathy. Other clinical features include fever, muscle, bone, and/or joint pain, and lymphadenopathy. About 15-20% of patients with Schnitzler syndrome develop lymphoproliferative diseases and, in rare cases, amyloid A (AA) amyloidosis can occur if the disease is not treated. Activation of the innate immune system, especially interleukin (IL)-1ß, is central to the pathogenesis of disease. Consequently, complete control of disease symptoms can be achieved in 80% of patients by treatment with the IL-1 receptor antagonist anakinra.

[Schnitzler syndrome]. / Schnitzler-Syndrom.

Schnitzler syndrome is a very rare acquired systemic disease with many similarities to hereditary autoinflammatory syndromes. The main characteristics are generalized exanthema and a monoclonal gammopathy with IgM. Other clinical features include fever, muscle, bone and/or joint pain, and lymphadenopathy. About 15-20% of patients with Schnitzler syndrome develop lymphoproliferative diseases and, in rare cases, amyloid A (AA) amyloidosis can occur if the disease is not treated. Activation of the innate immune system, especially interleukin(IL)-1ß, is central in the pathogenesis of the disease. Consequently, complete control of disease symptoms can be achieved in 80% of patients by treatment with the IL-1 receptor antagonist anakinra.

[Schnitzler syndrome]. / Schnitzler-Syndrom.

Schnitzler syndrome is a very rare acquired systemic disease with many similarities to hereditary autoinflammatory syndromes. The main characteristics are generalized exanthema and a monoclonal gammopathy with IgM. Other clinical features include fever, muscle, bone and/or joint pain, and lymphadenopathy. About 15-20% of patients with Schnitzler syndrome develop lymphoproliferative diseases and, in rare cases, amyloid A (AA) amyloidosis can occur if the disease is not treated. Activation of the innate immune system, especially interleukin(IL)-1ß, is central in the pathogenesis of the disease. Consequently, complete control of disease symptoms can be achieved in 80% of patients by treatment with the IL-1 receptor antagonist anakinra.

Mesenchymal Stromal Cells Protect Endothelial Cells from Cytotoxic T Lymphocyte-Induced Lysis.

The integrity of the vasculature plays an important role in the success of allogeneic organ and haematopoietic stem cell transplantation. Endothelial cells (EC) have previously been shown to be the target of activated cytotoxic T lymphocytes (CTL) resulting in extensive cell lysis. Mesenchymal stromal cells (MSC) are multipotent cells which can be isolated from multiple sites, each demonstrating immunomodulatory capabilities. They are explored herein for their potential to protect EC from CTL-targeted lysis. CD8(+) T cells isolated from human PBMC were stimulated with mitotically inactive cells of a human microvascular endothelial cell line (CDC/EU.HMEC-1, further referred to as HMEC) for 7 days. Target HMEC were cultured in the presence or absence of MSC for 24 h before exposure to activated allogeneic CTL for 4 h. EC were then analysed for cytotoxic lysis by flow cytometry. Culture of HMEC with MSC in the efferent immune phase (24 h before the assay) led to a decrease in HMEC lysis. This lysis was determined to be MHC Class I restricted linked and further analysis suggested that MSC contact is important in abrogation of lysis, as protection is reduced where MSC are separated in transwell experiments. The efficacy of multiple sources of MSC was also confirmed, and the collaborative effect of MSC and the endothelium protective drug defibrotide were determined, with defibrotide enhancing the protection provided by MSC. These results support the use of MSC as an adjuvant cellular therapeutic in transplant medicine, alone or in conjunction with EC protective agents such as defibrotide.

The prevalence of human papilloma virus (HPV) infections in oral squamous cell carcinomas: a retrospective analysis of 88 patients and literature overview.

In addition to tobacco and alcohol consumption, the two main risk factors for oral squamous cell carcinoma (OSCC), recent studies have revealed infections with human papilloma virus (HPV) as an additional risk factor for OSCC development. In the field of head and neck malignancies, the prevalence of HPV infections in oropharyngeal cancer (OC) ranges in different studies up to 84%. While HPV infection is discussed as an independent risk factor in this region, its distinguished role in carcinogenesis of tumours localized to the oral cavity remains still uncertain. In this study, we analysed the HPV status in 88 consecutive patients with OSCCs localized anterior of the palatoglossal arch who were treated in the Department of Oral and Maxillofacial Surgery at the University Medical Center Mainz. The HPV status analysis was performed using DNA-PCR and immunostaining of p16 protein. The prevalence of HPV-positive OSCCs was about 6% (5 patients). In 3 patients the HPV subtypes 16/18 were found. No significant differences between the HPV positive and negative patients regarding age, gender, smoking and alcohol consumption, localization and TNM level could be detected. Contrary to other studies focussing on cancers of the lingual and palatine tonsil, the prevalence of HPV infections was much lower in the oral cavity. Therefore HPV infection might play a less important role in oral carcinogenesis.

Fish oil supplementation induces expression of genes related to cell cycle, endoplasmic reticulum stress and apoptosis in peripheral blood mononuclear cells: a transcriptomic approach.

BACKGROUND: Fish oil supplementation has been shown to alter gene expression of mononuclear cells both in vitro and in vivo. However, little is known about the total transcriptome profile in healthy subjects after intake of fish oil. We therefore investigated the gene expression profile in peripheral blood mononuclear cells (PBMCs) after intake of fish oil for 7 weeks using transcriptome analyses. DESIGN: In a 7-week, double-blinded, randomized, controlled, parallel-group study, healthy subjects received 8 g day(-1) fish oil (1.6 g day(-1) eicosapentaenoic acid + docosahexaenoic acid) (n = 17) or 8 g day(-1) high oleic sunflower oil (n = 19). Microarray analyses of RNA isolated from PBMCs were performed at baseline and after 7 weeks of intervention. RESULTS: Cell cycle, DNA packaging and chromosome organization are biological processes found to be upregulated after intake of fish oil compared to high oleic sunflower oil using a moderated t-test. In addition, gene set enrichment analysis identified several enriched gene sets after intake of fish oil. The genes contributing to the significantly different gene sets in the subjects given fish oil compared with the control group are involved in cell cycle, endoplasmic reticulum (ER) stress and apoptosis. Gene transcripts with common motifs for 35 known transcription factors including E2F, TP53 and ATF4 were upregulated after intake of fish oil. CONCLUSION: We have shown that intake of fish oil for 7 weeks modulates gene expression in PBMCs of healthy subjects. The increased expression of genes related to cell cycle, ER stress and apoptosis suggests that intake of fish oil may modulate basic cellular processes involved in normal cellular function.

Induction of M2-macrophages by tumour cells and tumour growth promotion by M2-macrophages: a quid pro quo in pancreatic cancer.

INTRODUCTION: More effective therapies are required to improve survival of pancreatic cancer. Possible immunologic targets include tumour associated macrophages (TAMs), generally consisting of M1- and M2-macrophages. We have analysed the impact of TAMS on pancreatic cancer in a syngeneic orthotopic murine model. METHODS: 6606PDA murine pancreatic cancer cells were orthotopically injected into C57BL6 mice. Tumour growth was monitored using MRI. Macrophages were depleted by clodronate liposomes. Tumours including microvessel density were evaluated using immunohistochemistry, immunofluorescence and/or cytometric beads assays. Naïve macrophages were generated employing peritoneal macrophages. In vitro experiments included culturing of macrophages in tumour supernatants as well as tumour cells cultured in macrophage supernatants using arginase as well as Griess assays. RESULTS: Clodronate treatment depleted macrophages by 80% in livers (p = 0.0051) and by 60% in pancreatic tumours (p = 0.0169). MRI revealed tumour growth inhibition from 221.8 mm(3) to 92.3 mm(3) (p = 0.0216). Micro vessel densities were decreased by 44% (p = 0.0315). Yet, MCP-1-, IL-4- and IL-10-levels within pancreatic tumours were unchanged. 6606PDA culture supernatants led to a shift from naïve macrophages towards an M2-phenotype after a 36 h treatment (p < 0.0001), reducing M1-macrophages at the same time (p < 0.037). In vivo, M2-macrophages represented 85% of all TAMs (p < 0.0001). Finally, culture supernatants of M2-macrophages induced tumour growth in vitro by 63.2% (p = 0.0034). CONCLUSIONS: This quid pro quo of tumour cells and M2-macrophages could serve as a new target for future immunotherapies that interrupt tumour promoting activities of TAMs and change the iNOS-arginase balance towards their tumoricidal capacities.

Macrophages promote tumour growth and liver metastasis in an orthotopic syngeneic mouse model of colon cancer.

PURPOSE: Tumour-associated macrophages have been shown to promote proliferation, angiogenesis and metastasis in several carcinomas. The effect on colon cancer has not yet been clarified. Furthermore, Kupffer cells in the liver might initiate the formation of metastases by directly binding tumour cells. METHODS: An orthotopic syngeneic mouse model of colon cancer as well as a liver metastases model has been studied, using murine CT-26 colon cancer cells in Balb/c-mice. Macrophages were depleted in both models by clodronate liposomes. Tumour sizes and metastases were determined using 7-Tesla MRI. The macrophage and vascular density in the orthotopic tumours as well as the Kupffer cell density in the livers were evaluated using immunohistochemistry. RESULTS: Animals in the macrophage-depleted group displayed significantly smaller primary tumours (37 ± 20 mm(3)) compared to the control group (683 ± 389 mm(3), p = 0.0072). None of the mice in the depleted group showed liver or peritoneal metastases, whereas four of six control mice displayed liver and five out of six mice peritoneal metastases. The vascular density was significantly lower in the macrophage-depleted group (p = 0.0043). In the liver metastases model, animals of the Kupffer cell-depleted group (14.3 ± 7.7) showed significantly less liver metastases than mice of the two control groups (PBS liposomes, 118.5 ± 28.2, p = 0.0117; NaCl, 81.7 ± 23.2, p = 0.0266). The number of liver metastases correlated directly with the Kupffer cell density (p = 0.0221). CONCLUSION: Macrophages promote tumour growth, angiogenesis and metastases in this orthotopic syngeneic mouse model. Kupffer cells enhance the formation of metastases in the liver.

Familial chilblain lupus--a monogenic form of cutaneous lupus erythematosus due to a heterozygous mutation in TREX1.

Chilblain lupus erythematosus is a rare form of cutaneous lupus erythematosus characterized by bluish red infiltrates in acral locations of the body mostly affecting middle-aged women. We recently described a familial form of chilblain lupus manifesting in early childhood caused by a heterozygous mutation in the TREX1 gene, which encodes a 3'-5' DNA exonuclease. Thus, familial chilblain lupus represents the first monogenic form of cutaneous lupus erythematosus. Here we describe the unusual clinical course of this newly defined genodermatosis in an 18-year-old female member of the family in which familial chilblain lupus was originally described.

Image-guided lateral suboccipital approach: part 1-individualized landmarks for surgical planning.

OBJECTIVE: Being situated close to the transverse and sigmoid sinus, the asterion has traditionally been viewed as a landmark for surgical approaches to the posterior fossa. Cadaveric studies, however, have shown its variability in relation to underlying anatomic structures. We have used an image-guidance technology to determine the precise anatomic relationship between the asterion and the underlying transverse-sigmoid sinus transition (TST) complex in patients scheduled for posterior fossa surgery. The applicability of three-dimensional (3-D) volumetric image-rendering for presurgical anatomic identification and individualization of a surgical landmark was evaluated. METHODS: One-millimeter computed tomographic slices were combined with venous computed tomographic angiography in 100 patients, allowing for 3-D volumetric image-rendering of the cranial bone and the dural vasculature at the same time. The spatial relationship between the asterion and the TST was recorded bilaterally by using opacity modulation of the bony surface. The location of both the asterion and the TST could be confirmed during surgery in all of these patients. RESULTS: It was possible to accurately visualize the asterion and the sinuses in a single volumetrically rendered 3-D image in more than 90% of the patients. The variability in the anatomic position of the asterion as shown in cadaveric studies was confirmed, providing an individualized landmark for the patients. In this series, the asterion was located from 2 mm medial to 7 mm lateral and from 10 mm inferior to 17 mm superior to the TST, respectively. CONCLUSION: Volumetric image-rendering allows for precise in vivo measurements of anatomic distances in 3-D space. It is also a valuable tool for assessing the validity of traditional surgical landmarks and individualizing them for surgical planning.

Image-guided lateral suboccipital approach: part 2-impact on complication rates and operation times.

OBJECTIVE: Image-guidance systems are widely available for surgical planning and intraoperative navigation. Recently, three-dimensional volumetric image rendering technology that increasingly applies in navigation systems to assist neurosurgical planning, e.g., for cranial base approaches. However, there is no systematic clinical study available that focuses on the impact of this image-guidance technology on outcome parameters in suboccipital craniotomies. METHODS: A total of 200 patients with pathologies located in the cerebellopontine angle were reviewed, 100 of whom underwent volumetric neuronavigation and 100 of whom underwent treatment without intraoperative image guidance. This retrospective study analyzed the impact of image guidance on complication rates (venous sinus injury, venous air embolism, postoperative morbidity caused by venous air embolism) and operation times for the lateral suboccipital craniotomies performed with the patient in the semi-sitting position. RESULT: This study demonstrated a 4% incidence of injury to the transverse-sigmoid sinus complex in the image-guided group compared with a 15% incidence in the non-image-guided group. Venous air embolisms were detected in 8% of the image-guided patients and in 19% of the non-image-guided patients. These differences in terms of complication rates were significant for both venous sinus injury and venous air embolism (P < 0.05). There was no difference in postoperative morbidity secondary to venous air embolism between both groups. The mean time for craniotomy was 21 minutes in the image-guided group and 39 minutes in non-image-guided group (P = 0.036). CONCLUSION: Volumetric image guidance provides fast and reliable three-dimensional visualization of sinus anatomy in the posterior fossa, thereby significantly increasing speed and safety in lateral suboccipital approaches.

Key pinch in healthy adults: normative values.

Intra-individual and inter-individual variations of key pinch strength were analysed in a standardised manner for healthy Caucasian adults (female n = 403; male n = 366) aged between 20 and 95 years. The mean strength was less in women (right 6.6 kg; left 6.1 kg) than in men (right 10.4 kg; left 9.7 kg). Independently of hand dominance or gender, the right side was about 7% stronger. Constitutional variables such as forearm length, forearm circumference and hand size showed a positive correlation with key pinch strength. Since the correlation between age and key pinch was similar in both genders, showing a continuous decrease of strength from the fifth decade of life on, key pinch seems independent from gender-specific hormonal changes. In conclusion, we recommend to side adjust measured values and to include information regarding constitutional characteristics for intra-individual comparison.

Long-term follow-up of patients with pituitary macroadenomas after postoperative radiation therapy: analysis of tumor control and functional outcome.

PURPOSE: Evaluation of long-term tumor control, normalization of hormonal hypersecretion, including incidence and time course of pituitary dysfunction following postoperative radiotherapy of pituitary macroadenomas. PATIENTS AND METHODS: In a retrospective study, the data of 87 patients with pituitary macroadenomas (61 non-secreting adenomas, 26 secreting adenomas) treated between 1984 and 1994 were analyzed. All patients underwent surgery and received postoperative external-beam radiotherapy with a mean dose of 50.4 Gy (range 46-54 Gy). RESULTS: After a follow-up of 15 years the local tumor control rate achieved was 93.0% for non-secreting adenomas and 100% for secreting adenomas, respectively. Normalization of endocrine hypersecretion was noted in 24 of 26 patients (92%). Detailed endocrinological follow-up data were analyzed by an experienced endocrinologist in 77 patients. After a median follow-up of 10.54 years (mean 10.22; range 1.39-20.75 years), in 75 of 77 patients (97%) a hypopituitarism was observed (partial hypopituitarism, n = 28 [36%], panhypopituitarism, n = 47 [61%]), and 68 out of 77 patients (88%) showed evidence of radiotherapy-induced pituitary disorders. The somatotropic function was most commonly affected, followed by gonadal, thyroid and adrenal function. The gonadal axis showed to be the first to be disturbed. 67 patients (87%) required a hormone replacement therapy. CONCLUSION: Radiotherapy after pituitary surgery is highly effective in reducing hormonal hypersecretion and preventing recurrences of pituitary adenomas. However, pituitary insufficiencies are commonly observed after radiotherapy requiring a close follow-up to ensure timely diagnosis of pituitary dysfunction and an early inception of hormone replacement therapy.

Neuronavigational endoscopic endonasal sellar and parasellar surgery using a 2-mm-diameter lens rigid-rod endoscope: a cadaver study.

OBJECTIVE: Most of the endoscopes used for endonasal transsphenoidal surgery use 4-mm diameter lenses. The applicability of a newly developed neuroendoscope with a lens diameter of only 2 mm was tested in endonasal transsphenoidal pituitary surgery. METHODS: The newly developed rigid-rod neuroendoscope with a 2-mm lens and an endoscope with a 4-mm lens were coupled with a navigation system and used for this comparative study. Comparison between the views obtained with these two devices was performed in a model and in formalin-fixed cadaver heads. A pure endonasal approach was used to reach and explore the sellar and parasellar regions. The navigation system was used to locate the same position in both lenses for image comparison. RESULTS: The sellar and parasellar regions could be reached and explored using the new endoscope with the 2-mm lens and an oval-shaped irrigation and suction channel. The visual field appeared to be reduced compared with that of the 4-mm lens. However, this reduction was compensated by greater mobility and easier introduction and maneuvering of the instruments at the sellar level. Reduced image size and brightness were also found using the 2-mm lens compared with the 4-mm lens. These differences could be overcome by increasing the amount of light and enlarging the image but with subsequent reduction in image resolution. CONCLUSION: The small diameter of this neuroendoscope resulted in good maneuverability and maintained a fine quality of vision. Children and patients with small nostrils are good candidates for the use of such a device.

Role of bone morphogenetic protein 2 in the crosstalk between endothelial progenitor cells and mesenchymal stem cells.

In recent studies, we and others have demonstrated that bone morphogenetic protein-2 (BMP-2) promotes vascularization, inhibits hypoxic cell death of cancer cells and may be involved in tumor angiogenesis. The activation of circulating endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs) represents a crucial factor in the process of postnatal neovascularization. BMP-2 protein expression has been detected in several tumor tissues and BMP receptors are expressed in EPCs and MSCs. We therefore analysed the influence of recombinant human (rh) BMP-2 on the function of human EPCs and human bone marrow derived MSCs. Treatment of EPCs isolated from peripheral blood with rhBMP-2 did not induce any significant changes in EPC viability but induced a dose-dependent activation of chemotaxis. Incubation of human MSCs isolated from bone marrow aspirates with rhBMP-2 revealed no significant effect on MSC proliferation. Incubation of EPCs with supernatants of MSCs significantly increased the cell viability compared to controls cultivated with endothelial cell medium. Protein and mRNA expression of the vascular endothelial growth factor (VEGF) family member, placental growth factor (PlGF), which is known to be involved in the expansion and recruitment of EPCs, was induced in MSCs after treatment with rhBMP-2. We conclude that tumor- associated BMP-2 secretion might promote tumor angiogenesis by chemotactic effects on EPCs circulating in the peripheral blood and by increased secretion of paracrine angiogenic growth factors including PlGF in MSCs of the tumor stroma.

Neuronavigational neuroendoscopic surgery. Frameless free-hand maneuvering of a handy rigid-rod neuroendoscope on visualized three-dimensional computerized image guidance: trajectory to the prepontine cistern in cadaver study.

BACKGROUND: Considering the separate benefits of neuronavigation and neuroendoscopy, neuroendoscopic surgery with the aid of neuronavigation systems will play an increasingly important role in the future. Bearing this in mind, the present research project was conducted to facilitate neuronavigational neuroendoscopic surgery along the pathway to the prepontine cistern using cadaver heads. MATERIALS AND METHODS: A computer-aided, frameless image-guided stereotactic navigation system and a new type of handy rigid-rod neuroendoscope were used. The ideal entry point and the safest trajectory to the prepontine cistern through the foramen of Monro were defined in two formalin-fixed cadaver heads and clinical brain MRI data. Then, maneuvering of the neuroendoscope with the aid of the neuronavigation system was performed. RESULTS: Straight trajectories from the entry point to the prepontine cistern could be designed. For the registration accuracy of the tip of the neuroendoscope, the virtual image registered a mean error distance of 5.42 mm away from the reference point along the axis of vertical line. However, free-hand maneuvering enabled the neuroendoscope to be finely manipulated without damaging brain tissues. Neuroendoscopic anatomical views of the interpeduncular and prepontine cistern were also acquired. CONCLUSION: Interactive use of free-hand maneuvering of the handy rigid-rod neuroendoscope together with frameless neuronavigation systems plot the way to true neuronavigational neuroendoscopic surgery in a safe and reliable manner. This pairing of the most recent technological neurosurgical options with better understanding of neuroendoscopic anatomy enables the neurosurgeon to acquire broader treatment options for central nervous system diseases.