Stimulation of the vagus nerve as a therapeutic principle.

Modulation of the parasympathetic tone leads to extensive physiological reactions at several levels, including the decreased production of proinflammatory cytokines. Many studies have demonstrated that chronic inflammatory diseases are associated with reduced parasympathetic and increased sympathetic activities. Moreover, it was demonstrated that a low parasympathetic and a high sympathetic activity in patients with rheumatoid arthritis (RA) predicts a poor therapeutic response to anti-tumor necrosis factor (TNF) treatment compared to RA patients with a more balanced autonomic nervous system. The autonomic equilibrium could be restored by electrical stimulation of the vagus nerve. Considering the patients who do not sufficiently respond to the available drugs, patients for whom the effectiveness of the drugs wanes over time, or have drug-related adverse events, a nonpharmacological approach such as bioelectronics might be a useful supplement as an instrument in the successful extension of the therapeutic armamentarium for rheumatic diseases; however, there is a great need for further studies and the development of novel therapeutic strategies in the field of neuroimmunology.

[Stimulation of the vagus nerve as a therapeutic principle. German Version]. / Stimulation des Nervus vagus als therapeutisches Prinzip.

Modulation of the parasympathetic tone leads to extensive physiological reactions at several levels, including the decreased production of proinflammatory cytokines. Many studies have demonstrated that chronic inflammatory diseases are associated with reduced parasympathetic and increased sympathetic activities. Moreover, it was demonstrated that a low parasympathetic and a high sympathetic activity in patients with rheumatoid arthritis (RA) predicts a poor therapeutic response to anti-tumor necrosis factor (TNF) treatment compared to RA patients with a more balanced autonomic nervous system. The autonomic equilibrium could be restored by electrical stimulation of the vagus nerve. Considering the patients who do not sufficiently respond to the available drugs, patients for whom the effectiveness of the drugs wanes over time, or have drug-related adverse events, a nonpharmacological approach such as bioelectronics might be a useful supplement as an instrument in the successful extension of the therapeutic armamentarium for rheumatic diseases; however, there is a great need for further studies and the development of novel therapeutic strategies in the field of neuroimmunology.

Increased expression of LAT1 in basal cell carcinoma: implications for tumour cell survival.

BACKGROUND: Basal cell carcinoma (BCC) is the most common type of cancer in fair-skinned individuals worldwide. Altered metabolism is a hallmark of cancer, and a growing body of evidence has shown increased expression of the large neutral amino acid transporter small subunit 1 (LAT1) in several types of cancers, including BCC. However, the mechanisms behind changed LAT1 expression in BCC are largely unknown. AIM: To describe the protein expression of LAT1 and its colocalization with LAT2, and to examine LAT1 in association with BCC tumour biology characteristics such as cell proliferation, apoptosis and hypoxia. METHODS: Immunofluorescence stains were used on formalin-fixed, paraffin-embedded tissue samples (n = 14) from excised BCCs, and their protein-staining patterns were examined. RESULTS: There was no correlation between expression of LAT1 and LAT2, and the colocalization was low. Compared with normal epidermis, there was significantly higher expression in BCC tissue of the proliferation markers topoisomerase IIα (P < 0.01) and Ki-67 (P = 0.01). The fraction of LAT1-expressing cells in BCC tissue was significantly (P < 0.01) inversely correlated with the fraction of proliferative active tumour cells. Cleaved caspase-3 was significantly (P = 0.02) increased in tumour areas with high LAT1 expression. CONCLUSIONS: The present study shows that LAT1 is not usually expressed by proliferating BCC cells. The morphological localization suggests that tumour cells use LAT1 to adapt to environmental changes such as starvation and/or hypoxia. These findings could have implications for future development of LAT1-inhibitory BCC treatments.

Interaction of pain and chronic inflammation.

Rheumatic diseases are characterized by chronic inflammation of synovial joints and are often associated with persistent pain and increased pain sensitivity. The inflammatory process is a complex cascade of events involving several mediators, which can lead to a chronic condition of pain. Inflammation can stimulate angiogenesis, and angiogenesis can facilitate inflammation. Inflammatory pain arises from tissue damage via the sensitization of pain receptors (nociceptors). The main peripheral mechanism underlying nociceptive pain is a change in the activity of the nociceptors located in the affected anatomical structures (joints, tendons, and ligaments), which renders them more sensitive to normally painful stimuli (hyperalgesia) or normally non-painful stimuli (allodynia). Neuroimmune interaction has been considered to play an essential role in rheumatic disease. Neurogenic inflammation, which influences normal central nervous system signaling, leads to insufficient signaling/bioavailability of various cytokines. These central mechanisms play an important role in the increased pain sensitivity following inflammation and are responsible for the development of secondary hyperalgesia in regions beyond the injured tissue. Reduction of pain in rheumatic disease requires familiarity with various pain mechanisms.

Increased expression of Toll-like receptor 7 and 9 in vitiligo melanocytes: a pilot study.

BACKGROUND: Toll-like receptors (TLRs) are expressed on human melanocytes, and play an important role in innate and acquired immunity. The role of TLRs in the pathogenesis of vitiligo has not been fully described. AIM: To investigate the expression of TLRs in melanocytes from patients with vitiligo and healthy controls (HCs). METHODS: Primary cultured vitiligo and control melanocytes were obtained from perilesional normal skin of patients with generalized vitiligo and HCs. TLRs mRNA expression in melanocytes were determined by real-time reverse transcription PCR and protein expression by western blotting. Apoptosis was analysed using an annexin V-fluorescein isothiocyanate apoptosis detection kit, and tyrosinase activity and melanin content were measured by a modified dopachrome and colorimetric method. Interleukin (IL)-6, IL-8 and soluble cell adhesion molecule (sICAM)-1 expression were measured by ELISA. RESULTS: In vitiligo melanocytes, compared with control melanocytes, apoptosis rate, expression of TLR7 and TLR9 mRNA and protein, and production of IL-8, IL-6 and sICAM-1 were significantly increased, whereas tyrosinase activity and melanin content were significantly decreased. CONCLUSIONS: Our results suggest that the increased expression of TLR7 and TLR9 might correlate with melanocyte dysfunction in vitiligo.

Quality of life and contact with healthcare systems among patients with psoriasis and psoriatic arthritis: results from the NORdic PAtient survey of Psoriasis and Psoriatic arthritis (NORPAPP).

Psoriasis (skin psoriasis, PsO) is a chronic inflammatory condition. In about one-third of cases, the joints are affected (psoriatic arthritis, PsA). Both conditions, especially PsA, profoundly impact patients' health-related quality of life (HRQoL). To describe the impact of psoriasis on HRQoL and patients' contact with the healthcare system in Sweden, Denmark, and Norway, the NORdic PAtient survey of Psoriasis and Psoriatic arthritis (NORPAPP) asked 22,050 adults randomly selected in Sweden, Denmark and Norway if they had psoriasis. 1264 individuals who reported physician-diagnosed PsO/PsA were invited to the full survey; 1221 responded (74.6% diagnosed with PsO alone; 25.4% with PsA ± PsO). Respondents with PsA most frequently consulted a rheumatologist; however, 14.3% had never seen a rheumatologist. Respondents with PsO alone most frequently consulted a general practitioner and 10.7% had never seen a dermatologist (although those with severe symptoms visited dermatologists more often). Negative impacts on HRQoL were reported by 38.1% of respondents with PsO [mostly limitations on clothing (22.6%), sleep disorders (16%), and depression/anxiety (16%)] and by 73% of respondents with PsA [mostly limitations on clothing (41.8%), sports/leisure (44.0%), or daily routine (45.1%) and sleeping disorders]. Absence from work/education was more common with PsA ± PsO (51.9%) than PsO alone (15.1%). In this survey in Sweden, Denmark, and Norway, the impact of psoriasis on the respondents' HRQoL was profound and was greater for PsA than for PsO, as was sickness absence. Sleeping disorders and depression were common and should not be overlooked.

Treatment use and satisfaction among patients with psoriasis and psoriatic arthritis: results from the NORdic PAtient survey of Psoriasis and Psoriatic arthritis (NORPAPP).

BACKGROUND: There are scarce data in Scandinavia about treatment satisfaction among patients with psoriasis (PsO) and/or psoriatic arthritis (PsA). The number of patients receiving systemic treatment is unknown. OBJECTIVE: To describe patients' experience of treatments for PsO/PsA in Sweden, Denmark and Norway, addressing communication with physicians, satisfaction with treatment and concerns regarding treatment options. METHODS: The NORdic PAtient survey of Psoriasis and Psoriatic arthritis (NORPAPP) asked 22 050 adults (randomly selected from the YouGov panels in Sweden, Denmark and Norway) whether they had PsO/PsA. A total of 1264 individuals who reported physician-diagnosed PsO/PsA were invited to participate in the full survey; 96.6% responded positively. RESULTS: Systemic treatment use was reported by 14.6% (biologic: 8.1%) of respondents with PsO only and by 58.5% (biologic: 31.8%) of respondents with PsA. Biologic treatments were more frequently reported by respondents considering their disease severe (26.8% vs 6.7% non-severe) and those who were members of patient organizations (40.7% vs 6.9% non-members). Discussing systemic treatments with their physician was reported significantly more frequently by respondents with PsA, those perceiving their disease as severe (although 35.2% had never discussed systemic treatment with their physician) and those reporting being a member of a patient organization (P < 0.05). Many respondents reported health risk concerns and dissatisfaction with their treatment. Of special interest was that respondents aged 45-75 years reported less experience with biologics (8.1%) than those aged 18-44 years (21.5%). The older respondents also reported more uncertainty regarding long-term health risks related to systemic treatments (most [66.7-72.9%] responded 'do not know' when asked about the risk of systemic options). CONCLUSION: It appears likely that substantial numbers of Scandinavians suffering from severe PsO/PsA are not receiving optimal treatment from a patient perspective, particularly older patients. Also, one-third of respondents with severe symptoms had never discussed systemic treatment with a physician.

Insufficient vaccination rates in patients with systemic lupus erythematosus in a German outpatient clinic.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) are at an increased risk of acquiring infections due to the disease itself and the immunosuppressive therapy. Furthermore, infections largely contribute to overall SLE mortality. Vaccinations against preventable diseases are therefore of particular importance for these patients. AIMS: To estimate vaccination frequencies among patients with SLE, we studied patients in a survey and calculated vaccination rates based on their vaccination documents. Patients were recruited from our outpatient clinic during one of their routine visits. For the statistical analysis, they have been stratified by age (≥60 vs. <60 years) for further subgroup analysis due to age-related recommendations for some vaccines. RESULTS: Among the patients studied (n = 68) we found rather low vaccination rates in particular for the strongly recommended vaccines against pneumococcus and influenza (21% and 49%, respectively). Furthermore, protection rates for important basic vaccinations were found to be low, e. g. pertussis protection for 31% of patients. Beside these findings, we saw age-dependant differences for a variety of vaccines: while the pneumococcus vaccination was more often given to patients ≥60 years, measles, pertussis, diphtheria and hepatitis B vaccinations were found significantly more often in younger patients. CONCLUSIONS: Vaccination rates have to be improved among SLE patients, in particular for vaccines protecting from respiratory tract infections such as pneumococcus and influenza.

[Pilot Project: Improved Lung Deposition via a New Nasal Inhalation Procedure]. / Pilotprojekt zur verbesserten Lungendeposition durch ein neues Verfahren der nasalen Inhalation.

INTRODUCTION: Inhaled drugs can only be effective if they reach the middle and small airways. This study introduces a system that combines a trans-nasal application of aerosols with noninvasive pressure support ventilation. METHODS: In a pilot study, 7 COPD patients with GOLD stages II and III inhaled a radiolabeled marker dissolved in water via a trans-nasal route. The mean aerosol particle size was 5.5 µm. Each patient took part in two inhalation sessions that included two application methods and were at least 70 hours apart. During the first session ("passive method"), the patient inhaled the aerosol through an open tube system. The second session ("active method") included pressure support ventilation during the inhalation process. A gamma camera and planar scintigraphy was used to determine the distribution of aerosol particles in the patient's body and lung. RESULTS: The pressure supported inhalation ("active method") results in an increased aerosol lung deposition compared to the passive method. Above all, we could demonstrate deposition in the lung periphery with relatively large aerosol particles (5.5 µm). DISCUSSION: The results prove that the combination of trans-nasal inhalation with noninvasive pressure support ventilation leads to significantly increased particle deposition in the lung.

Superior antitumoral activity of dimerized targeted single-chain TRAIL fusion proteins under retention of tumor selectivity.

Although targeting of the death receptors (DRs) DR4 and DR5 still appears a suitable antitumoral strategy, the limited clinical responses to recombinant soluble TNF-related apoptosis inducing ligand (TRAIL) necessitate novel reagents with improved apoptotic activity/tumor selectivity. Apoptosis induction by a single-chain TRAIL (scTRAIL) molecule could be enhanced >10-fold by generation of epidermal growth factor receptor (EGFR)-specific scFv-scTRAIL fusion proteins. By forcing dimerization of scFv-scTRAIL based on scFv linker modification, we obtained a targeted scTRAIL composed predominantly of dimers (Db-scTRAIL), exceeding the activity of nontargeted scTRAIL ∼100-fold on Huh-7 hepatocellular and Colo205 colon carcinoma cells. Increased activity of Db-scTRAIL was also demonstrated on target-negative cells, suggesting that, in addition to targeting, oligomerization equivalent to an at least dimeric assembly of standard TRAIL per se enhances apoptosis signaling. In the presence of apoptosis sensitizers, such as the proteasomal inhibitor bortezomib, Db-scTRAIL was effective at picomolar concentrations in vitro (EC(50) ∼2 × 10(-12) M). Importantly, in vivo, Db-scTRAIL was well tolerated and displayed superior antitumoral activity in mouse xenograft (Colo205) tumor models. Our results show that both targeting and controlled dimerization of scTRAIL fusion proteins provides a strategy to enforce apoptosis induction, together with retained tumor selectivity and good in vivo tolerance.