Improvement of Restless Legs Syndrome Under Treatment of Cancer Pain With Morphine and Fentanyl

Restless-Legs-Syndrome (RLS), also known as Willis-Ekbom disease, is a sleep- and rest related disorder characterized by the unpleasant urge to move the legs. Pharmacological therapy is mainly based on dopamine-agonists and delta-2-alpha calcium channel ligands. Also, randomized-controlled-trials (RCTs) reported effectiveness of oral oxycodone (in combination with naloxone), and intrathecal opioids have also been administered for this indication. In the case reported here, a patient with advanced pancreatic cancer was referred to an acute palliative care unit for the treatment of cancer-related pain. Yet, in thorough exploration of her symptom burden, the patient reported that she felt her quality of life had been predominantly limited by symptoms other than cancer pain. Her medical history and neurological examination revealed that these symptoms were most obviously caused by severe RLS. In the years before, pharmacological therapies with dopamine-agonists and delta-2-alpha calcium channel ligands were initiated, but failed to relieve the RLS. In the palliative care ward, intravenous morphine was successfully titrated to treat her cancer pain. Concurrently, the patient also experienced almost complete relief from her RLS-symptoms and an increase in quality of life. The amelioration of her RLS-symptoms continued after morphine therapy was switched from intravenous to oral administration. Even after the patient was dismissed to home care and opioid rotation to transdermal fentanyl, symptom control of RLS remained excellent. To our knowledge, this is the first report of successfully treating RLS with intravenous and oral morphine. Since morphine is more easily available worldwide and the cost of morphine therapy is substantially lower compared to oxycodone/naloxone, comparisons to morphine may be an intriguing option for future RCTs

Deposition, Accumulation, and Alteration of Cl(-), NO3(-), ClO4(-) and ClO3(-) Salts in a Hyper-Arid Polar Environment: Mass Balance and Isotopic Constraints

The salt fraction in permafrost soils/sediments of the McMurdo Dry Valleys (MDV) of Antarctica can be used as a proxy for cold desert geochemical processes and paleoclimate reconstruction. Previous analyses of the salt fraction in MDV permafrost soils have largely been conducted in coastal regions where permafrost soils are variably affected by aqueous processes and mixed inputs from marine and stratospheric sources. We expand upon this work by evaluating permafrost soil/sediments in University Valley, located in the ultraxerous zone where both liquid water transport and marine influences are minimal. We determined the abundances of Cl(-), NO3(-, ClO4(-)and ClO3(-)in dry and ice-cemented soil/sediments, snow and glacier ice, and also characterized Cl(-) and NO3(-) isotopically. The data are not consistent with salt deposition in a sublimation till, nor with nuclear weapon testing fall-out, and instead point to a dominantly stratospheric source and to varying degrees of post depositional transformation depending on the substrate, from minimal alteration in bare soils to significant alteration (photodegradation and/or volatilization) in snow and glacier ice. Ionic abundances in the dry permafrost layer indicate limited vertical transport under the current climate conditions, likely due to percolation of snowmelt. Subtle changes in ClO4(-)/NO3(-) ratios and NO3(-) isotopic composition with depth and location may reflect both transport related fractionation and depositional history. Low molar ratios of ClO3(-)/ClO4(-) in surface soils compared to deposition and other arid systems suggest significant post depositional loss of ClO3(-), possibly due to reduction by iron minerals, which may have important implications for oxy-chlorine species on Mars. Salt accumulation varies with distance along the valley and apparent accumulation times based on multiple methods range from approximately 10 to 30 kyr near the glacier to 70-200 kyr near the valley mouth. The relatively young age of the salts and relatively low and homogeneous anion concentrations in the ice-cemented sediments point to either a mechanism of recent salt removal, or to relatively modern permafrost soils (less than 1 million years). Together, our results show that near surface salts in University Valley serve as an end-member of stratospheric sources not subject to biological processes or extensive remobilization

Mutations in multidomain protein MEGF8 identify a Carpenter syndrome subtype associated with defective lateralization

Carpenter syndrome is an autosomal-recessive multiple-congenital-malformation disorder characterized by multisuture craniosynostosis and polysyndactyly of the hands and feet; many other clinical features occur, and the most frequent include obesity, umbilical hernia, cryptorchidism, and congenital heart disease. Mutations of RAB23, encoding a small GTPase that regulates vesicular transport, are present in the majority of cases. Here, we describe a disorder caused by mutations in multiple epidermal-growth-factor-like-domains 8 (MEGF8), which exhibits substantial clinical overlap with Carpenter syndrome but is frequently associated with abnormal left-right patterning. We describe five affected individuals with similar dysmorphic facies, and three of them had either complete situs inversus, dextrocardia, or transposition of the great arteries; similar cardiac abnormalities were previously identified in a mouse mutant for the orthologous Megf8. The mutant alleles comprise one nonsense, three missense, and two splice-site mutations; we demonstrate in zebrafish that, in contrast to the wild-type protein, the proteins containing all three missense alterations provide only weak rescue of an early gastrulation phenotype induced by Megf8 knockdown. We conclude that mutations in MEGF8 cause a Carpenter syndrome subtype frequently associated with defective left-right patterning, probably through perturbation of signaling by hedgehog and nodal family members. We did not observe any subject with biallelic loss-of function mutations, suggesting that some residual MEGF8 function might be necessary for survival and might influence the phenotypes observed

TRPP2 and TRPV4 form a polymodal sensory channel complex

The primary cilium has evolved as a multifunctional cellular compartment that decorates most vertebrate cells. Cilia sense mechanical stimuli in various organs, but the molecular mechanisms that convert the deflection of cilia into intracellular calcium transients have remained elusive. Polycystin-2 (TRPP2), an ion channel mutated in polycystic kidney disease, is required for cilia-mediated calcium transients but lacks mechanosensitive properties. We find here that TRPP2 utilizes TRPV4 to form a mechano- and thermosensitive molecular sensor in the cilium. Depletion of TRPV4 in renal epithelial cells abolishes flow-induced calcium transients, demonstrating that TRPV4, like TRPP2, is an essential component of the ciliary mechanosensor. Because TRPV4-deficient zebrafish and mice lack renal cysts, our findings challenge the concept that defective ciliary flow sensing constitutes the fundamental mechanism of cystogenesis

Characterization of highly stable liposomal and immunoliposomal formulations of vincristine and vinblastine

Liposome and immunoliposome formulations of two vinca alkaloids, vincristine and vinblastine, were prepared using intraliposomal triethylammonium sucroseoctasulfate and examined for their ability to stabilize the drug for targeted drug delivery in vivo. The pharmacokinetics of both the encapsulated drug (vincristine or vinblastine) and liposomal carrier were examined in Sprague Dawley rats, and the in vivo drug release rates determined. Anti-HER2 immunoliposomal vincristine was prepared from a human anti-HER2/neu scFv and studied for targeted cytotoxic activity in cell culture, and antitumor efficacy in vivo. Nanoliposome formulations of vincristine and vinblastine demonstrated similar pharmacokinetic profiles for the liposomal carrier, but increased clearance for liposome encapsulated vinblastine (t 1/2 = 9.7 h) relative to vincristine (t 1/2 = 18.5 h). Immunoliposome formulations of vincristine targeted to HER2 using an anti-HER2 scFv antibody fragment displayed a marked enhancement in cytotoxicity when compared to non-targeted liposomal vincristine control; 63- or 253-fold for BT474 and SKBR3 breast cancer cells, respectively. Target-specific activity was also demonstrated in HER2-overexpressing human tumor xenografts, where the HER2-targeted formulation was significantly more efficacious than either free vincristine or non-targeted liposomal vincristine. These results demonstrate that active targeting of solid tumors with liposomal formulations of vincristine is possible when the resulting immunoliposomes are sufficiently stabilized

Lessons Learned from Introducing Last Aid Courses at a University Hospital in Germany

In recent years, so called “Last Aid courses”, concerning end-of-life care for people dying, have successfully been established in community settings in several European countries, Australia, and South-America. To date, they have not been evaluated in hospital settings, where educational needs (concerning care of the dying) are especially high, and may differ from the general population. To evaluate if Last Aid courses are feasible in hospital settings, and if informational needs of hospital staff are met by the curriculum, we introduced Last Aid courses at a university hospital. Five courses were offered; participants of courses 1 and 2 completed surveys with open-ended questions; the answers were used to develop the evaluation questionnaire employed in courses 3–5. In these three courses, 55 of the 56 participants completed an evaluation survey to explore their learning goals and obtain feedback. Courses were fully booked; participants were heterogeneous with regard to their professional background. The most prevalent learning goals were “preparation for emotional aspects in care of dying” (65.5% ratings “very important”), “preparation for medical/care aspects in care of dying” (60.0%), and “knowledge of supportive services and facilities” (54.5%). Overall, the evaluation showed that Last Aid courses were more suitable to educate non-medical hospital staff about care of the dying. Medical staff, in contrast to non-medical staff, more often requested courses with an extended curriculum in order to meet their learning goals. Last Aid courses were well accepted and helped to reduce information deficits on care of the dying in a heterogeneous population of hospital staff

Implementation of an acute palliative care unit for COVID-19 patients in a tertiary hospital: Qualitative data on clinician perspectives

Background: During the COVID-19 pandemic, it has become apparent that palliative care has dynamically adapted to the care of dying patients with and without COVID-19 and has developed new forms of collaboration. Evaluation is needed to assess which innovations should be integrated into future pandemic management. Aim: To explore the experiences of stakeholders and staff in implementing and operating an ad hoc unit delivering acute palliative care. What lessons were learned? Design: Qualitative interview study (German Clinical Trials Register; identifier 22,473) with qualitative content analysis. Setting/participants: During the first wave of the pandemic, the University Medical Center Freiburg (Germany) established an ad hoc unit delivering acute palliative care for COVID-19 patients likely to die. Nurses from non-palliative areas and the specialist palliative care team formed a new team working together there. Twenty-nine individuals from management and staff of this unit were interviewed. Results: Patient care and teamwork were rated positively. Joint familiarization, bedside teaching, and team/management support were evaluated as core elements for success. Challenges for the nurses from non-palliative settings included adapting to palliative care routines and culture of care. The palliative care team had to adjust the high standards of palliative care to pandemic conditions. Due to sufficient hospital-wide capacity, only three COVID-19 patients were treated, significantly fewer than anticipated at planning. Conclusions: Results show the feasibility of an ad hoc COVID-19 acute palliative care unit. In the event of capacity constraints, such a unit can be a viable part of future pandemic management

Kif3a Guides Microtubular Dynamics, Migration and Lumen Formation of MDCK Cells

The microtubular motor Kinesin-2 and its subunit Kif3a are essential for the formation of primary cilia, an organelle implicated in a wide spectrum of developmental abnormalities. Outside cilia, Kinesin-2 mediated transport has been implicated in vesicle and N-cadherin transport, but it is unknown if and how extraciliary Kif3a affects basic cellular functions such as migration or the formation of multicellular structures. Here we show that tetracycline inducible depletion of Kif3a in MDCK cells slows epithelial cell migration. Microtubules at the leading edge of Kif3a depleted cells failed to grow perpendicularly into the leading edge and microtubular dynamics were dampened in Kif3a depleted cells. Loss of Kif3a retarded lateral membrane specification and completely prevented the formation of three-dimensional spheres in collagen. These data uncover that Kif3a regulates the microtubular cytoskeleton in the cell periphery and imply that extra-ciliary Kif3a has an unexpected function in morphogenesis