A Smart Skin for Hydrogels That Enables Switchable Solute Release.

Many applications of hydrogels rely on their ability to deliver encapsulated solutes, such as drugs; however, small hydrophilic solutes rapidly leak out of gels by diffusion. A need exists for a way to regulate solute release out of gels─to ensure zero release until a desired time (the OFF state) and thereafter for the release to be switched ON at a high rate. This should ideally be a repeatable switch; i.e., the gel should be cyclable repeatedly between the ON and OFF states. Such perfect, cyclical ON-OFF release of solutes from gels is demonstrated for the first time through a "smart skin" that is synthesized rapidly (in ∼10 min) around an entire gel. The thin (∼100 µm) and transparent polymer skin is endowed with redox-responsive properties through the use of urethane and acrylate monomers, one of which contains a thioether group. Initially, the skin is hydrophobic (water contact angle 102°), and it completely prevents hydrophilic solutes from leaking out of the gel. When contacted with oxidants such as hydrogen peroxide (H2O2), the thioethers are converted to sulfoxides, making the skin hydrophilic (water contact angle 42°) and thereby turning ON the release of solutes. Conversely, solute release can be turned OFF subsequently by adding a reducing agent such as vitamin C that reverts the sulfoxides to thioethers and thus returns the skin to its hydrophobic state. The release rate in the ON state can be tuned via the skin thickness as well as the oxidant concentration. The ability to regulate solute delivery from gels using smart skins is likely to prove significant in areas ranging from separations to agriculture and drug delivery.

Direct Potential Modulation of Neurogenic Differentiation Markers by Granulocyte-Colony Stimulating Factor (G-CSF) in the Rodent Brain.

The hematopoietic granulocyte-colony stimulating growth factor (G-CSF, filgrastim) is an approved drug in hematology and oncology. Filgrastim's potential in neurodegenerative disorders is gaining increasingly more attention, as preclinical and early clinical studies suggest it could be a promising treatment option. G-CSF has had a tremendous record as a safe drug for more than three decades; however, its effects upon the central nervous system (CNS) are still not fully understood. In contrast to conceptual long-term clinical application with lower dosing, our present pilot study intends to give a first insight into the molecular effects of a single subcutaneous (s.c.) high-dose G-CSF application upon different regions of the rodent brain. We analyzed mRNA-and in some instances-protein data of neurogenic and non-neurogenic differentiation markers in different regions of rat brains five days after G-CSF (1.3 mg/kg) or physiological saline. We found a continuous downregulation of several markers in most brain regions. Remarkably, cerebellum and hypothalamus showed an upregulation of different markers. In conclusion, our study reveals minor suppressive or stimulatory effects of a single exceptional high G-CSF dose upon neurogenic and non-neurogenic differentiation markers in relevant brain regions, excluding unregulated responses or unexpected patterns of marker expression.

Validation of the psychometric properties of a "Modified Version of the Hornheider Screening Instrument" (HSI-MV) using a sample of outpatient and inpatient skin tumor patients.

BACKGROUND: The basis for adequate psycho-oncological care is the identification of patients with psychosocial support needs. The German Working Group for Psychooncology also recommends the Hornheider Screening Instrument (HSI) for this purpose. The question, "Is anyone in your family particularly burdened by the hospital stay?" is intended to capture disease-related family stress. But is this item equally suitable for outpatients and inpatients? The study objective was to examine how replacing the original item affects the test performance of this modified version of the HSI and the frequency of psychosocial stress. PATIENTS AND METHODS: 92 outpatients and 98 inpatients with skin tumors assessed their psychosocial situation using different questionnaires. RESULTS: Compared to inpatients, less than half as many outpatients answered the item in the affirmative. If the question was replaced by: "Is someone in your family particularly burdened by your disease or the course of the disease?" this setting-related difference did not arise. The "Alternative item" and the "Modified version of the HIS" (HSI-MV) proved to be superior to the original item and the original HSI with regard to all examined criteria. CONCLUSIONS: The HSI-MV can be used as a reliable and valid instrument for the systematic assessment of psychosocial care needs in outpatient and inpatient settings. Depending on care capacity, a threshold of ≥ 5 or ≥ 4 is appropriate. In addition to screening, the desire for support should be enquired.

COVID-19 impact on teleactivities: Role of built environment and implications for mobility.

This paper presents new evidence on changes in a broad range of teleactivities due to the Coronavirus disease (COVID-19) pandemic and investigates how the built environment relates to these changes. The paper relies on survey and geospatial data from Oslo and its surrounding Viken region in Norway. Findings suggest that most teleactivities increased due to COVID-19. Telework, teleconferencing, online learning, telehealth, and virtual meetings with friends and family all increased during COVID-19 compared to the pre-COVID-19 period. The next step in the analysis examined relationships between built environment characteristics and teleactivities before and during COVID-19. Telework and virtual meetings increased to a greater extent in denser neighborhoods than in lower-density neighborhoods. A larger increase in online learning was associated with lower neighborhood density, lower accessibility to public transport, and more local facilities. Numerous local facilities were associated with more frequent telework and virtual meetings both before and during COVID-19. The substantial COVID-19-induced increase in teleactivities found in the study highlights the potential of information and communications technology (ICT) for replacing travel for various activities.

Safe and Effective Cynomolgus Monkey GLP-Tox Study with Repetitive Intrathecal Application of a TGFBR2 Targeting LNA-Gapmer Antisense Oligonucleotide as Treatment Candidate for Neurodegenerative Disorders.

The capability of the adult central nervous system to self-repair/regenerate was demonstrated repeatedly throughout the last decades but remains in debate. Reduced neurogenic niche activity paralleled by a profound neuronal loss represents fundamental hallmarks in the disease course of neurodegenerative disorders. We and others have demonstrated the endogenous TGFß system to represent a potential pathogenic participant in disease progression, of amyotrophic lateral sclerosis (ALS) in particular, by generating and promoting a disequilibrium of neurodegenerative and neuroregenerative processes. The novel human/primate specific LNA Gapmer Antisense Oligonucleotide "NVP-13", targeting TGFBR2, effectively reduced its expression and lowered TGFß signal transduction in vitro and in vivo, paralleled by boosting neurogenic niche activity in human neuronal progenitor cells and nonhuman primate central nervous system. Here, we investigated NVP-13 in vivo pharmacology, safety, and tolerability following repeated intrathecal injections in nonhuman primate cynomolgus monkeys for 13 weeks in a GLP-toxicology study approach. NVP-13 was administered intrathecally with 1, 2, or 4 mg NVP-13/animal within 3 months on days 1, 15, 29, 43, 57, 71, and 85 in the initial 13 weeks. We were able to demonstrate an excellent local and systemic tolerability, and no adverse events in physiological, hematological, clinical chemistry, and microscopic findings in female and male Cynomolgus Monkeys. Under the conditions of this study, the no observed adverse effect level (NOAEL) is at least 4 mg/animal NVP-13.

Chronic oxytocin-driven alternative splicing of Crfr2α induces anxiety.

The neuropeptide oxytocin (OXT) has generated considerable interest as potential treatment for psychiatric disorders, including anxiety and autism spectrum disorders. However, the behavioral and molecular consequences associated with chronic OXT treatment and chronic receptor (OXTR) activation have scarcely been studied, despite the potential therapeutic long-term use of intranasal OXT. Here, we reveal that chronic OXT treatment over two weeks increased anxiety-like behavior in rats, with higher sensitivity in females, contrasting the well-known anxiolytic effect of acute OXT. The increase in anxiety was transient and waned 5 days after the infusion has ended. The behavioral effects of chronic OXT were paralleled by activation of an intracellular signaling pathway, which ultimately led to alternative splicing of hypothalamic corticotropin-releasing factor receptor 2α (Crfr2α), an important modulator of anxiety. In detail, chronic OXT shifted the splicing ratio from the anxiolytic membrane-bound (mCRFR2α) form of CRFR2α towards the soluble CRFR2α (sCRFR2α) form. Experimental induction of alternative splicing mimicked the anxiogenic effects of chronic OXT, while sCRFR2α-knock down reduced anxiety-related behavior of male rats. Furthermore, chronic OXT treatment triggered the release of sCRFR2α into the cerebrospinal fluid with sCRFR2α levels positively correlating with anxiety-like behavior. In summary, we revealed that the shifted splicing ratio towards expression of the anxiogenic sCRFR2α underlies the adverse effects of chronic OXT treatment on anxiety.

Reconditioning the Neurogenic Niche of Adult Non-human Primates by Antisense Oligonucleotide-Mediated Attenuation of TGFß Signaling.

Adult neurogenesis is a target for brain rejuvenation as well as regeneration in aging and disease. Numerous approaches showed efficacy to elevate neurogenesis in rodents, yet translation into therapies has not been achieved. Here, we introduce a novel human TGFß-RII (Transforming Growth Factor-Receptor Type II) specific LNA-antisense oligonucleotide ("locked nucleotide acid"-"NVP-13"), which reduces TGFß-RII expression and downstream receptor signaling in human neuronal precursor cells (ReNcell CX® cells) in vitro. After we injected cynomolgus non-human primates repeatedly i.th. with NVP-13 in a preclinical regulatory 13-week GLP-toxicity program, we could specifically downregulate TGFß-RII mRNA and protein in vivo. Subsequently, we observed a dose-dependent upregulation of the neurogenic niche activity within the hippocampus and subventricular zone: human neural progenitor cells showed significantly (up to threefold over control) enhanced differentiation and cell numbers. NVP-13 treatment modulated canonical and non-canonical TGFß pathways, such as MAPK and PI3K, as well as key transcription factors and epigenetic factors involved in stem cell maintenance, such as MEF2A and pFoxO3. The latter are also dysregulated in clinical neurodegeneration, such as amyotrophic lateral sclerosis. Here, we provide for the first time in vitro and in vivo evidence for a novel translatable approach to treat neurodegenerative disorders by modulating neurogenesis.

Modeling and Bioinformatics Identify Responders to G-CSF in Patients With Amyotrophic Lateral Sclerosis.

Objective: Developing an integrative approach to early treatment response classification using survival modeling and bioinformatics with various biomarkers for early assessment of filgrastim (granulocyte colony stimulating factor) treatment effects in amyotrophic lateral sclerosis (ALS) patients. Filgrastim, a hematopoietic growth factor with excellent safety, routinely applied in oncology and stem cell mobilization, had shown preliminary efficacy in ALS. Methods: We conducted individualized long-term filgrastim treatment in 36 ALS patients. The PRO-ACT database, with outcome data from 23 international clinical ALS trials, served as historical control and mathematical reference for survival modeling. Imaging data as well as cytokine and cellular data from stem cell analysis were processed as biomarkers in a non-linear principal component analysis (NLPCA) to identify individual response. Results: Cox proportional hazard and matched-pair analyses revealed a significant survival benefit for filgrastim-treated patients over PRO-ACT comparators. We generated a model for survival estimation based on patients in the PRO-ACT database and then applied the model to filgrastim-treated patients. Model-identified filgrastim responders displayed less functional decline and impressively longer survival than non-responders. Multimodal biomarkers were then analyzed by PCA in the context of model-defined treatment response, allowing identification of subsequent treatment response as early as within 3 months of therapy. Strong treatment response with a median survival of 3.8 years after start of therapy was associated with younger age, increased hematopoietic stem cell mobilization, less aggressive inflammatory cytokine plasma profiles, and preserved pattern of fractional anisotropy as determined by magnetic resonance diffusion tensor imaging (DTI-MRI). Conclusion: Long-term filgrastim is safe, is well-tolerated, and has significant positive effects on disease progression and survival in a small cohort of ALS patients. Developing and applying a model-based biomarker response classification allows use of multimodal biomarker patterns in full potential. This can identify strong individual treatment responders (here: filgrastim) at a very early stage of therapy and may pave the way to an effective individualized treatment option.

Antisense Oligonucleotide in LNA-Gapmer Design Targeting TGFBR2-A Key Single Gene Target for Safe and Effective Inhibition of TGFß Signaling.

Antisense Oligonucleotides (ASOs) are an emerging drug class in gene modification. In our study we developed a safe, stable, and effective ASO drug candidate in locked nucleic acid (LNA)-gapmer design, targeting TGFß receptor II (TGFBR2) mRNA. Discovery was performed as a process using state-of-the-art library development and screening. We intended to identify a drug candidate optimized for clinical development, therefore human specificity and gymnotic delivery were favored by design. A staggered process was implemented spanning in-silico-design, in-vitro transfection, and in-vitro gymnotic delivery of small batch syntheses. Primary in-vitro and in-vivo toxicity studies and modification of pre-lead candidates were also part of this selection process. The resulting lead compound NVP-13 unites human specificity and highest efficacy with lowest toxicity. We particularly focused at attenuation of TGFß signaling, addressing both safety and efficacy. Hence, developing a treatment to potentially recondition numerous pathological processes mediated by elevated TGFß signaling, we have chosen to create our data in human lung cell lines and human neuronal stem cell lines, each representative for prospective drug developments in pulmonary fibrosis and neurodegeneration. We show that TGFBR2 mRNA as a single gene target for NVP-13 responds well, and that it bears great potential to be safe and efficient in TGFß signaling related disorders.

Effects of continuous high-dose G-CSF administration on hematopoietic stem cell mobilization and telomere length in patients with amyotrophic lateral sclerosis - a pilot study.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of complex and still poorly understood etiology. Loss of upper and lower motoneurons results in death within few years after diagnosis. Recent studies have proposed neuroprotective and disease-slowing effects of granulocyte-colony stimulating factor (G-CSF) treatment in ALS mouse models as well as humans. In this study, six ALS patients were monitored up to 3.5 years during continuous high-dose G-CSF administration. Repetitive analyses were performed including blood count parameters, CD34+ hematopoietic stem and progenitor cell (HSPC) and colony forming cell (CFC) counts, serum cytokine levels and leukocyte telomere length. We demonstrate that continuous G-CSF therapy was well tolerated and safe resulting in only mild adverse events during the observation period. However, no mobilization of CD34+ HSPC was detected as compared to baseline values. CFC mobilization was equally low and even a decrease of myeloid precursors was observed in some patients. Assessment of telomere length within ALS patients' leukocytes revealed that G-CSF did not significantly shorten telomeres, while those of ALS patients were shorter compared to age-matched healthy controls, irrespective of G-CSF treatment. During G-CSF stimulation, TNF-alpha, CRP, IL-16, sVCAM-1, sICAM-1, Tie-2 and VEGF were significantly increased in serum whereas MCP-1 levels decreased. In conclusion, our data show that continuous G-CSF treatment fails to increase circulating CD34+ HSPC in ALS patients. Cytokine profiles revealed G-CSF-mediated immunomodulatory and proteolytic effects. Interestingly, despite intense G-CSF stimulation, telomere length was not significantly shortened.

Sensory contact to the stressor prevents recovery from structural and functional heart damage following psychosocial trauma.

Cardiovascular disorders (CVD) and posttraumatic stress disorder (PTSD) are highly comorbid, but the underlying mechanisms are not fully understood. Chronic psychosocial stress was induced in male mice by chronic subordinate colony housing (CSC), a pre-clinically validated mouse model for PTSD. Cardiac structure and function were assessed on day 20 of the CSC paradigm. Following CSC, mice were kept in different sensory contact modalities to the last aggressor for 30 days, and development of cardiac function and behavioral aspects were determined. Here we show that psychosocial trauma affects heart structure by disturbing cell-to-cell integrity of cardiomyocytes, causes tachycardia, disturbance of diurnal heart rate rhythmicity and behavioral deficits in a mouse model for PTSD. Structural and functional alterations were also found in cardiomyocytes upon in vitro treatment with pro-inflammatory cytokines typically increased after psychosocial trauma. Interestingly, sensory contact to the aggressor subsequent to psychosocial trauma prohibits functional and structural heart recovery, while isolation was beneficial for cardiac but detrimental for mental health. These findings contribute to our understanding of potential mechanisms underlying the high comorbidity of CVD and PTSD.

Biomarker Supervised G-CSF (Filgrastim) Response in ALS Patients.

Objective: To evaluate safety, tolerability and feasibility of long-term treatment with Granulocyte-colony stimulating factor (G-CSF), a well-known hematopoietic stem cell factor, guided by assessment of mobilized bone marrow derived stem cells and cytokines in the serum of patients with amyotrophic lateral sclerosis (ALS) treated on a named patient basis. Methods: 36 ALS patients were treated with subcutaneous injections of G-CSF on a named patient basis and in an outpatient setting. Drug was dosed by individual application schemes (mean 464 Mio IU/month, range 90-2160 Mio IU/month) over a median of 13.7 months (range from 2.7 to 73.8 months). Safety, tolerability, survival and change in ALSFRS-R were observed. Hematopoietic stem cells were monitored by flow cytometry analysis of circulating CD34+ and CD34+CD38- cells, and peripheral cytokines were assessed by electrochemoluminescence throughout the intervention period. Analysis of immunological and hematological markers was conducted. Results: Long term and individually adapted treatment with G-CSF was well tolerated and safe. G-CSF led to a significant mobilization of hematopoietic stem cells into the peripheral blood. Higher mobilization capacity was associated with prolonged survival. Initial levels of serum cytokines, such as MDC, TNF-beta, IL-7, IL-16, and Tie-2 were significantly associated with survival. Continued application of G-CSF led to persistent alterations in serum cytokines and ongoing measurements revealed the multifaceted effects of G-CSF. Conclusions: G-CSF treatment is feasible and safe for ALS patients. It may exert its beneficial effects through neuroprotective and -regenerative activities, mobilization of hematopoietic stem cells and regulation of pro- and anti-inflammatory cytokines as well as angiogenic factors. These cytokines may serve as prognostic markers when measured at the time of diagnosis. Hematopoietic stem cell numbers and cytokine levels are altered by ongoing G-CSF application and may potentially serve as treatment biomarkers for early monitoring of G-CSF treatment efficacy in ALS in future clinical trials.

Fulminant Acute Ascending Hemorrhagic Myelitis Treated with Eculizumab.

We describe an 18-year-old patient who developed back pain, rapidly ascending sensomotory deficits, bladder dysfunction, Lhermitte's sign, absent abdominal reflexes of all three levels, brisk tendon reflexes, and positive Babinski's sign. Magnetic resonance imaging of the spinal cord showed a long segment of cervical and thoracic intramedullary signal hyperintensity suggesting a longitudinally extensive transverse myelitis possibly within the course of a fast progressing ascending immune-mediated hemorrhagic myelopathy. Throughout his illness, the patient deteriorated with tetraplegia, cardiac arrest, and respiratory failure although he received, after exclusion of infective causes, therapy with steroids, immunoglobulins, plasmapheresis, and cyclophosphamide. Interestingly, treatment with the C5-inhibitor eculizumab to prevent complement-mediated spinal cord injury achieved an arrest of clinical deterioration. We propose eculizumab as treatment in fast progressive and potentially fatal immune-mediated spinal cord injury. Furthermore, this case raises awareness for the process of clinical decision-making in severe myelopathies.

The TGF-ß System As a Potential Pathogenic Player in Disease Modulation of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) represents a fatal orphan disease with high unmet medical need, and a life time risk of approx. 1/400 persons per population. Based on increasing knowledge on pathophysiology including genetic and molecular changes, epigenetics, and immune dysfunction, inflammatory as well as fibrotic processes may contribute to the heterogeneity and dynamics of ALS. Animal and human studies indicate dysregulations of the TGF-ß system as a common feature of neurodegenerative disorders in general and ALS in particular. The TGF-ß system is involved in different essential developmental and physiological processes and regulates immunity and fibrosis, both affecting neurogenesis and neurodegeneration. Therefore, it has emerged as a potential therapeutic target for ALS: a persistent altered TGF-ß system might promote disease progression by inducing an imbalance of neurogenesis and neurodegeneration. The current study assessed the activation state of the TGF-ß system within the periphery/in life disease stage (serum samples) and a late stage of disease (central nervous system tissue samples), and a potential influence upon neuronal stem cell (NSC) activity, immune activation, and fibrosis. An upregulated TGF-ß system was suggested with significantly increased TGF-ß1 protein serum levels, enhanced TGF-ß2 mRNA and protein levels, and a strong trend toward an increased TGF-ß1 protein expression within the spinal cord (SC). Stem cell activity appeared diminished, reflected by reduced mRNA expression of NSC markers Musashi-1 and Nestin within SC-paralleled by enhanced protein contents of Musashi-1. Doublecortin mRNA and protein expression was reduced, suggesting an arrested neurogenesis at late stage ALS. Chemokine/cytokine analyses suggest a shift from a neuroprotective toward a more neurotoxic immune response: anti-inflammatory chemokines/cytokines were unchanged or reduced, expression of proinflammatory chemokines/cytokines were enhanced in ALS sera and SC postmortem tissue. Finally, we observed upregulated mRNA and protein expression for fibronectin in motor cortex of ALS patients which might suggest increased fibrotic changes. These data suggest that there is an upregulated TGF-ß system in specific tissues in ALS that might lead to a "neurotoxic" immune response, promoting disease progression and neurodegeneration. The TGF-ß system therefore may represent a promising target in treatment of ALS patients.

Oxytocin inhibits ethanol consumption and ethanol-induced dopamine release in the nucleus accumbens.

Alcohol (EtOH) is one of the most widely abused recreational drugs and is arguably the most harmful. However, current treatment options for alcohol-use disorders generally have limited efficacy and poor uptake in the community. In this context, the neuropeptide oxytocin (OXT) has emerged as a promising potential treatment option for a number of substance-use disorders, including alcoholism. The utility of OXT in reducing consumption of and craving for a wide range of substances may lie in its ability to modulate drug-induced neurochemical effects within the mesolimbic dopamine pathway. However, the impact of OXT on EtOH actions in this pathway has yet to be explored. Here, we reveal that an acute intracerebroventricular (icv) infusion of OXT (1 µg/5 µl) attenuated voluntary EtOH (20 percent) self-administration after chronic intermittent access to EtOH for 59 days (28 drinking sessions) in male Wistar rats. Next, we demonstrated that an acute intraperitoneal (ip) injection of EtOH (1.5 g/kg, 15 percent w/v) increased dopamine release within the nucleus accumbens in both EtOH-naive rats and rats that had received 10 daily ip injections of EtOH. Icv OXT completely blocked the EtOH-induced dopamine release in both EtOH-naive and chronically treated rats. The attenuation of EtOH-induced dopamine release by OXT may help to explain the reduced EtOH self-administration observed following icv OXT infusion.

The Granulocyte-colony stimulating factor has a dual role in neuronal and vascular plasticity.

Granulocyte-colony stimulating factor (G-CSF) is a growth factor that has originally been identified several decades ago as a hematopoietic factor required mainly for the generation of neutrophilic granulocytes, and is in clinical use for that. More recently, it has been discovered that G-CSF also plays a role in the brain as a growth factor for neurons and neural stem cells, and as a factor involved in the plasticity of the vasculature. We review and discuss these dual properties in view of the neuroregenerative potential of this growth factor.

Serious Games for Home-based Stroke Rehabilitation.

On average, two thousand residents in the United States experience a stroke every day. These circumstances account for $28 billion direct costs annually and given the latest predictions, these costs will more than triple by 2030. In our research, we propose a portfolio of serious games for home-based stroke rehabilitation. The objective of the game approach is to enrich the training experience and establish a higher level of compliance to prescribed exercises, while maintaining a supportive training environment as found in common therapy sessions. Our system provides a collection of mini games based on rehabilitation exercises used in conventional physical therapy, monitors the patient's performance while exercising and provides clinicians with an interface to personalize the training. The clinician can set the current state of rehabilitation and change the playable games over time to drive diversification. While the system still has to be evaluated, an early stage case study with one patient offered positive indications towards this concept.

Oxytocin prevents ethanol actions at δ subunit-containing GABAA receptors and attenuates ethanol-induced motor impairment in rats.

Even moderate doses of alcohol cause considerable impairment of motor coordination, an effect that substantially involves potentiation of GABAergic activity at δ subunit-containing GABA(A) receptors (δ-GABA(A)Rs). Here, we demonstrate that oxytocin selectively attenuates ethanol-induced motor impairment and ethanol-induced increases in GABAergic activity at δ-GABA(A)Rs and that this effect does not involve the oxytocin receptor. Specifically, oxytocin (1 µg i.c.v.) given before ethanol (1.5 g/kg i.p.) attenuated the sedation and ataxia induced by ethanol in the open-field locomotor test, wire-hanging test, and righting-reflex test in male rats. Using two-electrode voltage-clamp electrophysiology in Xenopus oocytes, oxytocin was found to completely block ethanol-enhanced activity at α4ß1δ and α4ß3δ recombinant GABA(A)Rs. Conversely, ethanol had no effect when applied to α4ß1 or α4ß3 cells, demonstrating the critical presence of the δ subunit in this effect. Oxytocin had no effect on the motor impairment or in vitro effects induced by the δ-selective GABA(A)R agonist 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, which binds at a different site on δ-GABA(A)Rs than ethanol. Vasopressin, which is a nonapeptide with substantial structural similarity to oxytocin, did not alter ethanol effects at δ-GABA(A)Rs. This pattern of results confirms the specificity of the interaction between oxytocin and ethanol at δ-GABA(A)Rs. Finally, our in vitro constructs did not express any oxytocin receptors, meaning that the observed interactions occur directly at δ-GABA(A)Rs. The profound and direct interaction observed between oxytocin and ethanol at the behavioral and cellular level may have relevance for the development of novel therapeutics for alcohol intoxication and dependence.

The anterior supine intermuscular approach for total hip arthroplasty: reducing the complication rate by improving the procedure.

This study describes specific complications noticed during the first unselected cases operated by anterior approach for THA in our hospital and specific adjustments that were applied on the procedure to prevent these complications. We retrospectively analysed the differences between 202 patients who were operated by a standardised approach and 248 patients who were operated after adjustments were implemented with the procedure. Injury to the lateral femoral cutaneous nerve (LFCN), fractures of the greater trochanter and dislocation were specific complications that were noticed with the initial technique.Prevalence of injury to the LFCN decreased from 7.9% to 0.8% (p<0.001), fractures of the greater trochanter decreased from 5.4% to 0.8% (p = 0.004) and the incidence of dislocation decreased from 4.5% to 1.6% (p = 0.074).