Photoprotection against UVAR: effective triterpenoids require a lipid raft stabilizing chemical structure

Abstract: UVA(Ultraviolet A)‐induced gene expression is supposed to be a hallmark for inflammation, for immunosuppression and in long‐term cancer formation. In previous studies, we have shown for keratinocytes that physiological doses of UVA radiation result in the upregulation of gene expression mediated by ceramide formation from sphingolipids/cholesterol‐rich microdomains (rafts), which can be blocked by preloading keratinocytes with cholesterol or plant sterols. Here, we show that besides stigmasterol and ß‐sitosterol, also sterols like 14‐dehydroergosterol, ergosterol‐peroxide and 29‐norcycloartenol inhibit the UVA response. Moreover, we present evidence that natural material‐derived triterpenoids such as oleanolic acid can abrogate UVA‐induced gene expression by raft stabilization. This effect depends on the structure of the molecule, because its isomer ursolic acid also integrates within the rafts without inhibiting ceramide formation and upregulation of gene expression.     

Long-term functional outcome and quality of life in patients with high imperforate anus

Purpose

Anorectal malformations (ARMs) are associated with a large number of functional sequale that may affect a child's long-term quality of life (QOL). The purposes of this study were to better quantify patient functional stooling outcome and to identify how these outcomes related to the QOL in patients with high imperforate anus.

Methods

Forty-eight patients from 2 children's hospitals underwent scoring of stooling after 4 years of life. Scoring consisted of a 13-item questionnaire to assess long-term stooling habits (score range: 0-30, worst to best). These results were then correlated with a QOL survey as judged by a parent or guardian.

Result

Mean (SD) age at survey was 6.5 (1.6) years. Comparison of QOL and clinical scoring showed no signficant difference between the 2 institutions (P > .05). There was a direct correlation between the QOL and stooling score (Pearson r² = 0.827; β coefficient = 24.7, P < .001). Interestingly, functional stooling scores worsened with increasing age (Pearson r² = 0.318, P = .02). Patients with associated congenital anomalies had a high rate of poor QOL (44% in poor range; P = .001). Stooling scores decreased significantly with increasing severity/complexity of the ARM (P = .001).

Conclusion

A large number of children experience functional stooling problems, and these were directly associated with poor QOL. In contrast to previous perceptions, our study showed that stooling patterns are perceived to worsen with age. This suggests that children with ARMs need long-term follow-up and counseling.     

Functional interaction between trace amine-associated receptor 1 and dopamine D2 receptor

The ability of dopamine receptors to interact with other receptor subtypes may provide mechanisms for modulating dopamine-related functions and behaviors. In particular, there is evidence suggesting that the trace amine-associated receptor 1 (TAAR1) affects the dopaminergic system by regulating the firing rate of dopaminergic neurons or by altering dopamine D2 receptor (D2R) responsiveness to ligands. TAAR1 is a Gα(s) protein-coupled receptor that is activated by biogenic amines, "trace amines," such as β-phenylethylamine (β-PEA) and tyramine that are normally found at low concentrations in the mammalian brain. In the present study, we investigated the biochemical mechanism of interaction between TAAR1 and D2R and the role this interaction plays in D2R-related signaling and behaviors. Using a bioluminescence resonance energy transfer biosensor for cAMP, we demonstrated that the D2R antagonists haloperidol, raclopride, and amisulpride were able to enhance selectively a TAAR1-mediated β-PEA increase of cAMP. Moreover, TAAR1 and D2R were able to form heterodimers when coexpressed in human embryonic kidney 293 cells, and this direct interaction was disrupted in the presence of haloperidol. In addition, in mice lacking TAAR1, haloperidol-induced striatal c-Fos expression and catalepsy were significantly reduced. Taken together, these data suggest that TAAR1 and D2R have functional and physical interactions that could be critical for the modulation of the dopaminergic system by TAAR1 in vivo.     

Step activity monitoring in lumbar stenosis patients undergoing decompressive surgery

Symptomatic degenerative central lumbar spinal stenosis (LSS) is a frequent indication for decompressive spinal surgery, to reduce spinal claudication. No data are as yet available on the effect of surgery on the level of activity measured with objective long-term monitoring. The aim of this prospective, controlled study was to objectively quantify the level of activity in central LSS patients before and after surgery, using a continuous measurement device. The objective data were correlated with subjective clinical results and the radiographic degree of stenosis. Forty-seven patients with central LSS and typical spinal claudication scheduled for surgery were included. The level of activity (number of gait cycles) was quantified for 7 consecutive days using the StepWatch Activity Monitor (SAM). Visual analogue scales (VAS) for back and leg pain, Oswestry disability index and Roland–Morris score were used to assess the patients’ clinical status. The patients were investigated before surgery and 3 and 12 months after surgery. In addition, the radiographic extent of central LSS was measured digitally on preoperative magnetic resonance imaging or computed tomography. The following results were found preoperatively: 3,578 gait cycles/day, VAS for back pain 5.7 and for leg pain 6.5. Three months after surgery, the patients showed improvement: 4,145 gait cycles/day, VAS for back pain 4.0 and for leg pain 3.0. Twelve months after surgery, the improvement continued: 4,335 gait cycles/day, VAS for back pain 4.1 and for leg pain 3.3. The clinical results and SAM results showed significant improvement when preoperative data were compared with data 3 and 12 months after surgery. The results 12 months after surgery did not differ significantly from those 3 months after surgery. The level of activity correlated significantly with the degree of leg pain. The mean cross-sectional area of the spinal canal at the central LSS was 94 mm². The radiographic results did not correlate either with objective SAM results or with clinical outcome parameters. In conclusion, this study is the first to present objective data on continuous activity monitoring/measurements in patients with central LSS. The SAM could be an adequate tool for performing these measurements in spine patients. Except for leg pain, the objective SAM results did not correlate with the clinical results or with the radiographic extent of central LSS.     

Spinal cord constraints in the era of high-precision radiotherapy

Objective

Current constraints aim to minimize the risk of radiation myelitis by the use of restrictive maximal spinal cord doses, commonly 50?Gy. However, several studies suggested that a dose–volume effect could exist. Based on these observations, we evaluated patients receiving potentially excessive doses to the spinal cord within minimal volumes.

Patients and methods

Patients receiving radiotherapy between June 2010 and May 2015 using the Novalis^TM (Varian, Palo Alto, CA, USA; Brainlab, Heimstetten, Germany) radiosurgery system were retrospectively analyzed. A total of 56 patients with 62 treated lesions that had been prescribed radiation doses close to the spinal cord potentially higher than the common 50?Gy 2?Gy equivalent-dose (EQD2) constraint were selected for further analysis. Of these patients, 26 with 31 lesions had no history of previous irradiation, while 30 patients with 31 lesions had been previously irradiated within the treatment field.

Results

According to different dose evaluation approaches (spinal canal, spinal cord contour), 16 and 10 out of 31 primary irradiated lesions infringed constraints. For the 16 lesions violating spinal canal doses, the maximum doses ranged from 50.5 to 61.9?Gy EQD2. Reirradiated lesions had an average and median cumulative dose of 70.5 and 69?Gy, respectively. Dose drop-off was steep in both groups. Median overall survival was 17 months. No radiation myelitis or radiomorphological alterations were observed during follow-up.

Conclusion

This study adds to the increasing body of evidence indicating that excessive spinal cord doses within a minimal volume, especially in a reirradiation setting with topographically distinct high-point doses, may be given to patients after careful evaluation of treatment- and tumor-associated risks.

     

Autoimmune pancreatitis: Multimodality non-invasive imaging diagnosis

Autoimmune pancreatitis(AIP)is characterized by obstructive jaundice,a dramatic clinical response to steroids and pathologically by a lymphoplasmacytic infiltrate,with or without a pancreatic mass.Type 1AIP is the pancreatic manifestation of an Ig G4-related systemic disease and is characterized by elevated Ig G4serum levels,infiltration of Ig G4-positive plasma cells and extrapancreatic lesions.Type 2 AIP usually has none or very few Ig G4-positive plasma cells,no serum Ig G4 elevation and appears to be a pancreas-specific disorder without extrapancreatic involvement.AIP is diagnosed in approximately 2%-6%of patients that undergo pancreatic resection for suspected pancreatic cancer.There are three patterns of autoimmune pancreatitis:diffuse disease is the most common type,with a diffuse,“sausage-like”pancreatic enlargement with sharp margins and loss of the lobular contours;focal disease is less common and manifests as a focal mass,often within the pancreatic head,mimicking a pancreatic malignancy.Multifocal involvement can also occur.In this paper we describe the features of AIP at ultrasonography,computed tomography,magnetic resonanceand positron emission tomography/computed tomography imaging,focusing on diagnosis and differential diagnosis with pancreatic ductal adenocarcinoma.It is of utmost importance to make an early correct differential diagnosis between these two diseases in order to identify the optimal therapeutic strategy and to avoid unnecessary laparotomy or pancreatic resection in AIP patients.Non-invasive imaging plays also an important role in therapy monitoring,in follow-up and in early identification of disease recurrence.     

Molecular composition and functional properties of f-channels in murine embryonic stem cell-derived pacemaker cells

Mouse embryonic stem cells (mESCs) differentiate into all cardiac phenotypes, and thus represent an important potential source for cardiac regenerative therapies. Here we characterize the molecular composition and functional properties of “funny” (f-) channels in mESC-derived pacemaker cells. Following differentiation, a fraction of mESC-derived myocytes exhibited action potentials characterized by a slow diastolic depolarization and expressed the I_f current. I_f plays an important role in the pacemaking mechanism of these cells since ivabradine (3 μM), a specific f-channel inhibitor, inhibited I_f by about 50% and slowed rate by about 25%. Analysis of I_f kinetics revealed the presence of two populations of cells, one expressing a fast- and one a slow-activating I_f; the two components are present both at early and late stages of differentiation and had also distinct activation curves. Immunofluorescence analysis revealed that HCN1 and HCN4 are the only isoforms of the pacemaker channel expressed in these cells. Rhythmic cells responded to β-adrenergic and muscarinic agonists: isoproterenol (1 μM) accelerated and acetylcholine (0.1 μM) slowed spontaneous rate by about 50 and 12%, respectively. The same agonists caused quantitatively different effects on I_f: isoproterenol shifted activation curves by about 5.9 and 2.7 mV and acetylcholine by − 4.0 and − 2.0 mV in slow and fast I_f-activating cells, respectively. Accordingly, β1- and β2-adrenergic, and M2-muscarinic receptors were detected in mESC-derived myocytes. Our data show that mESC-derived pacemaker cells functionally express proteins which underlie generation and modulation of heart rhythm, and can therefore represent a potential cell substrate for the generation of biological pacemakers.     

Preference for weekly and monthly bisphosphonates among patients with postmenopausal osteoporosis: results from the Croatian PROMO Study

The PROMO (preference for once monthly bisphosphonate) Study, conducted in seven hospital centres in Croatia between June 2007 and June 2008, was designed to analyse patient preference for weekly and monthly bisphosphonates in everyday clinical practice where the significant proportion of patients are not completely satisfied with the current osteoporosis treatment. Eligible participants were women with postmenopausal osteoporosis taking weekly bisphosphonates for the last 6 months. Those who agreed to be enrolled were transferred from weekly to monthly ibandronate for the next 6 months. There was no washout period between the two treatment regimens. At the baseline, patients expressed their satisfaction with the weekly treatment. At the end of the study, all patients were asked to complete the five-question survey specially designed for this study. Study population comprised 258 participants. Among 248 patients who completed the study, 244 (98.4%) declared their preference for one of the regimens or they had no preference. Once-monthly regimen was preferred by 231 patients (94.7%), whereas once-weekly regimen was preferred by five patients (2.0%). Eight patients (3.3%) indicated no preference. Furthermore, 93.0% of patients thought that monthly dosing was more convenient. Compared to weekly regimen, monthly dosing was associated with significantly higher satisfaction with the treatment and with significantly less adverse events. In line with these data, 85.9% of patients stated improved quality of life with monthly ibandronate. In summary, the PROMO Study demonstrated strong patient preference for monthly over weekly dosing which is expected to improve suboptimal adherence to weekly bisphosphonates.