Methylphenidate-induced increases in vesicular dopamine sequestration and dopamine release in the striatum: the role of muscarinic and dopamine D2 receptors

Methylphenidate (MPD) administration alters the subcellular distribution of vesicular monoamine transporter-2 (VMAT-2)-containing vesicles in rat striatum. This report reveals previously undescribed pharmacological features of MPD by elucidating its receptor-mediated effects on VMAT-2-containing vesicles that cofractionate with synaptosomal membranes after osmotic lysis (referred to herein as membrane-associated vesicles) and on striatal dopamine (DA) release. MPD administration increased DA transport into, and decreased the VMAT-2 immunoreactivity of, the membrane-associated vesicle subcellular fraction. These effects were mimicked by the D2 receptor agonist quinpirole and blocked by the D2 receptor antagonist eticlopride. Both MPD and quinpirole increased vesicular DA content. However, MPD increased, whereas quinpirole decreased, K(+)-stimulated DA release from striatal suspensions. Like MPD, the muscarinic receptor agonist, oxotremorine, increased K(+)-stimulated DA release. Both eticlopride and the muscarinic receptor antagonist scopolamine blocked MPD-induced increases in K(+)-stimulated DA release, whereas the N-methyl-d-aspartate receptor antagonist (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) was without effect. This suggests that D2 receptors mediate both the MPD-induced redistribution of vesicles away from synaptosomal membranes and the MPD-induced up-regulation of vesicles remaining at the membrane. This results in a redistribution of DA within the striatum from the cytoplasm into vesicles, leading to increased DA release. However, D2 receptor activation alone is not sufficient to mediate the MPD-induced increases in striatal DA release because muscarinic receptor activation is also required. These novel findings provide insight into the mechanism of action of MPD, regulation of DA sequestration/release, and treatment of disorders affecting DA disposition, including attention-deficit hyperactivity disorder, substance abuse, and Parkinson's disease.     

Implementing decision and communication aids to facilitate patient-centered care in breast cancer: A case study

Objective

Decision Services (DS) provide support for breast cancer patients at the University of California, San Francisco to help ensure patient-centered care.

Methods

We examined a case study to explore whether our program practices matched our program theory, and what the patient in the case thought was effective and ineffective about our decision support interventions.

Results

The patient relied on a decision aid to educate her husband about her condition; felt that her question list contributed to a productive and efficient consultation with her oncologist; credited an audio-recording with helping her remember to follow-up with a genetic counselor; and reviewed the consultation summary 30 days into treatment in order to reflect on her decision. The patient rated the interventions highly on surveys, and experienced desirable reductions in decisional conflict, and improvements in knowledge. However, the question-prompting intervention was associated with a small decrease in self-efficacy, and the patient criticized the decision aid for omitting mention of a prognostic test.

Conclusion

This case illustrates how decision support interventions can be deployed to promote patient-centered care.

Practice implications

Breast care centers should consider distributing decision aids and assisting patients in listing questions, recording consultations, and obtaining written consultation summaries.     

Predicting chemical impacts on vertebrate endocrine systems

Animals have evolved diverse protective mechanisms for responding to toxic chemicals of both natural and anthropogenic origin. From a governmental regulatory perspective, these protective responses complicate efforts to establish acceptable levels of chemical exposure. To explore this issue, we considered vertebrate endocrine systems as potential targets for environmental contaminants. Using the hypothalamic-pituitary-thyroid (HPT), hypothalamic-pituitary-gonad (HPG), and hypothalamic-pituitary-adrenal (HPA) axes as case examples, we identified features of these systems that allow them to accommodate and recover from chemical insults. In doing so, a distinction was made between effects on adults and those on developing organisms. This distinction was required because endocrine system disruption in early life stages may alter development of organs and organ systems, resulting in permanent changes in phenotypic expression later in life. Risk assessments of chemicals that impact highly regulated systems must consider the dynamics of these systems in relation to complex environmental exposures. A largely unanswered question is whether successful accommodation to a toxic insult exerts a fitness cost on individual animals, resulting in adverse consequences for populations. Mechanistically based mathematical models of endocrine systems provide a means for better understanding accommodation and recovery. In the short term, these models can be used to design experiments and interpret study findings. Over the long term, a set of validated models could be used to extrapolate limited in vitro and in vivo testing data to a broader range of untested chemicals, species, and exposure scenarios. With appropriate modification, Tier 2 assays developed in support of the U.S. Environmental Protection Agency's Endocrine Disruptor Screening Program could be used to assess the potential for accommodation and recovery and inform the development of mechanistically based models.     

Verrucous carcinoma in epidermolysis bullosa simplex is possibly associated with a novel mutation in the keratin 5 gene

Epidermolysis bullosa simplex (EBS) is mainly caused by mutations in the KRT5 and KRT14 genes. Squamous cell carcinoma (SCC) represents the second most frequent skin neoplasia with complex aetiology. The molecular events disrupting the orchestrated interplay between the cytoskeleton, cell adhesion molecules and signalling proteins are ill understood in SCC. We describe the molecular background and the unusual course of the disease in a patient with EBS Dowling–Meara, severe keratoderma and a massive verrucous carcinoma. Skin and tumour samples from the patient were analysed using light microscopy, immunohistochemistry and immunofluorescence mapping. Mutation analysis of the KRT5 and KRT14 genes identified the novel KRT5 mutation p.E477D. Invasive tumour areas were characterized by downregulation of keratins 5 and 14, reduced and irregular desmocollin‐2 expression and increased expression of keratins 6, 16 and 17. Levels of Ki‐67 were increased and levels of E‐cadherin strongly reduced in the tumour tissue. In this case a novel KRT5 mutation led to increased fragility of keratinocytes. Desmosome and adherens junctions were destabilized, which may trigger keratinocyte‐mediated inflammation, possibly via p120‐catenin‐dependent signalling, suggesting a link between a keratin mutation and SCC, which adds weight to the hypothesis that disturbance of the cytoskeleton represents a major cause in the appearance of the malignant phenotype. Some individuals with EBS may be at risk of developing secondary SCC.     

Differential effects of Zn2+ on the kinetics and cocaine inhibition of dopamine transport by the human and rat dopamine transporters

Zn2+ may play a major role in the modulation of neurotransmission because it modulates membrane receptors and channels. Recent literature has shown Zn2+ inhibits dopamine transport by the dopamine transporter (DAT), the main target of cocaine and some other drugs of abuse. Cocaine inhibits DAT and modulation of the DAT by Zn2+ may alter effects of cocaine on dopamine neurotransmission. This study investigates how Zn2+ changes DAT kinetics and its inhibition by cocaine. Steady-state and pre-steady-state kinetics of DAT activity were investigated using rotating disk electrode voltammetry. Values of KM and Vmax in hDAT and effects of cocaine match those in the literature. Zn2+ allosterically inhibited transport in the human DAT (hDAT) with a KI=7.9+/-0.42 microM. Removal of endogenous Zn2+ with penicillamine in hDAT increased transport values. In contrast, Zn2+ did not alter transport by rat DAT (rDAT), with KM and Vmax values of 1.2+/-0.49 microM and 15.7+/-2.57 pmol/(sx10(6) cells), respectively, and removal of Zn2+ did not increase dopamine transport values. Zn2+ allosterically reduced the inhibition by cocaine in hDAT. Results of pre-steady-state studies demonstrated that Zn2+ increases the second order binding rate constant for dopamine to hDAT (3.5 fold to 19.2x10(6) M-1 s-1 for hDAT). In rat striatal homogenates Zn2+ increased initial dopamine transport velocity and decreased cocaine inhibition providing evidence for differences in sensitivity to Zn2+ between the three different preparations. Modulation of the DAT by Zn2+ needs to be assessed further in development of cocaine antagonists.     

Perioperative antibiotic prophylaxis in skin surgery – Position paper of the Antibiotic Stewardship working group of the German Society for Dermatologic Surgery (DGDC), Part 2: Special indications and situations

In addition to prevention of surgical site infections after skin surgery, perioperative antibiotic prophylaxis (PAP) aims to prevent the occurrence of other postoperative infectious complications, especially bacterial endocarditis and hematogenous joint prosthesis infections. This article discusses specific indications for the use of PAP. For example, patients who have undergone any type of heart valve replacement, including transcatheter valve replacement or use of prosthetic material to correct the heart valve, or patients who have experienced bacterial endocarditis, require PAP during skin surgery on mucosal membranes or ulcerated tumors. The use of PAP in special situations such as secondary wound healing, septic dermatosurgery or ulcer surgery is also presented and discussed in detail in this paper based on the current scientific literature. This paper represents the second part of the position paper of the Antibiotic Stewardship Working Group of the German Society for Dermatologic Surgery (DGDC) and summarizes evidence-based recommendations for the administration of PAP during skin surgery for special indications and situations. This is particularly important because, as detailed in Part 1 of this position paper, PAP can and usually should be avoided in skin surgery.     

Beneficial effects of Silexan on co-occurring depressive symptoms in patients with subthreshold anxiety and anxiety disorders: randomized,placebo-controlled trials revisited

European Archives of Psychiatry and Clinical Neuroscience - Silexan is a proprietary active substance produced from Lavandula angustifolia, with proven anxiolytic efficacy in subthreshold and...     

Penile fractures: the price of a merry Christmas

Objectives

To explore whether Christmas might be a risk factor for penile fractures due to the Christmas spirit related to the intimacy and euphoria of these holly jolly days.

Patients and methods

We evaluated the incidence of penile fractures during Christmas and New Year's Eve through the GeRmAn Nationwide inpatient Data (GRAND) from the Research Data Center of the Federal Bureau of Statistics (Wiesbaden, Germany). Furthermore, we assessed the impact of COVID-19 on penile fractures and their seasonality.

Results

A total of 3,421 patients with a median, interquartile range (IQR) age of 42 (32–51) years had a penile fracture requiring a hospital stay from 2005 to 2021. In all, 40 (1.2%) penile fractures occurred in 51 days of Christmas (from 24/12 to 26/12 in each year). The daily incidence of penile fractures during Christmas was 0.78 with an incidence rate ratio (IRR) of 1.43 (95% confidence interval [CI] 1.05–1.95, P = 0.02). If every day was like Christmas, 43% more penile fractures would have occurred in Germany from 2005 on. Interestingly, only 28 (0.82%) penile fractures occurred during the New Year's Eve period (31/12 to 02/01 from 2005 to 2021). This resulted in an IRR of 0.98 (95% CI 0.69–1.5, P = 0.98) in the New Year's Eve period. Most patients with penile fractures were admitted to hospital at the weekend (n = 1,322; IRR 1.58, 95% CI 1.48–1.69; P < 0.001). Summer was also associated with more penile fractures (n = 929; IRR 1.11, 95% CI 1.03–1.19; P = 0.008). Both the COVID-19 pandemic (n = 385; IRR 1.06, 95% CI 0.95–1.18, P = 0.29) and its lockdown period (n = 93; IRR 1, 95% CI 0.82–1.23; P = 0.96) did not affect the incidence of penile fractures.

Conclusion

The incidence of penile fractures displays a seasonality. Last Christmas penile fractures occurred more often. This year to save us from tears, we will NOT do something special (the new Christmas hit of the year).