Prevalence of Vitamin D Deficiency and Its Relationship with Clinical Outcomes in Patients with Fibromyalgia: a Systematic Review of the Literature

Fibromyalgia is a debilitating chronic condition which poses a therapeutic challenge to the clinician. With a large backlog in patient flow subsequent to the COVID-19 pandemic and rising numbers of patients with post-acute sequelae of COVID-19 (PASC) presenting with fibromyalgia-like clinical features, there is an increasingly pressing need to identify broad cost-effective interventions. Low levels of vitamin D have previously been reported in patients with fibromyalgia, though any causative link has been difficult to establish. A systematic literature review on the association between vitamin D deficiency and fibromyalgia was performed examining retrospective evidence both for and against an association between vitamin D deficiency (VDD) and fibromyalgia and evaluating the therapeutic benefit from supplementation. A group of six studies were selected based on relevance, use of controls, quality of research and citations. Four primary studies assessing the prevalence of VDD in fibromyalgia patients versus controls were evaluated with a total 3,496 subjects. Three included females only and one larger study assessed males. Two (n = 313) concluded the presence of a statistically significant association, and two (n = 161) found none. Two randomised controlled trials assessing the effect of vitamin D supplementation in a total of 80 subjects found conflicting results, with pain reduction in one and none in the other. It is likely there exists an association between VDD deficiency and fibromyalgia in a large subset of patients, although establishing primary causation is difficult. There is a need for larger randomised controlled trial designs with more effective comparison with healthy subjects and control for confounding factors. Given VDD is a major problem in the general population, we recommend supplementation be recommended by healthcare professionals to fibromyalgia patients for the purpose of maintaining bone health given their potentially increased susceptibility to developing deficiency and its sequelae.

The Renaissance of Cyclin Dependent Kinase Inhibitors

Cyclin-dependent kinases (CDK) regulate cell cycle progression. During tumor development, altered expression and availability of CDKs strongly contribute to impaired cell proliferation, a hallmark of cancer. In recent years, targeted inhibition of CDKs has shown considerable therapeutic benefit in a variety of tumor entities. Their success is reflected in clinical approvals of specific CDK4/6 inhibitors for breast cancer. This review provides a detailed insight into the molecular mechanisms of CDKs as well as a general overview of CDK inhibition. It also summarizes the latest research approaches and current advances in the treatment of head and neck cancer with CDK inhibitors. Instead of monotherapies, combination therapies with CDK inhibitors may especially provide promising results in tumor therapy. Indeed, recent studies have shown a synergistic effect of CDK inhibition together with chemo- and radio- and immunotherapy in cancer treatment to overcome tumor evasion, which may lead to a renaissance of CDK inhibitors.

The Functional Psychotherapy Approach: A Process-Outcome Multiple Case Study

Objective: The present work aims to conduct the first naturalistic empirical investigation of the process and outcome assessment of functional psychotherapy (FP) treatment. The FP model of psychotherapy is rooted in psychoanalysis and integrates the verbal communication approach founded on transference and countertransference dynamics with the analysis of bodily processes.Method: The study sample included ten patients recruited on a voluntary basis and treated by clinicians in their private practices. Each patient received FP with an average duration of 40 h (min 35 and max 42). Therapies had weekly sessions, were audio-recorded with the patient’s written consent, and lasted for an average of 10 months (min 9 and max 12). Outcome and process tools included the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) and the Luborsky’s the Core Conflictual Relationship Theme (CCRT), used to assess therapeutic benefit, and the Metacognition Assessment Scale (MAS) and the Italian Discourse Attributes Analysis Program (IDAAP) system, used to evaluate therapeutic benefit and process. The MMPI-2 was used also in the follow-up assessment.Results: Results show that FP had a positive therapeutic outcome on the patients assessed in this study, and that the therapeutic benefits were maintained over time. Some specific features of the FP approach were found to contribute more than others to the observed therapeutic benefits.Conclusion: The current investigation constitutes a first step toward assessment of the therapeutic effectiveness of FP. Future developments should apply the methodology to a larger sample, possibly introducing different methodologies to enable detection of specific bodily oriented processes and techniques.

Aromatherapy in Textiles: A Systematic Review of Studies Examining Textiles as a Potential Carrier for the Therapeutic Effects of Essential Oils

Integrative medicine is a rapidly growing specialty field of medical care that emphasizes the amalgamation of complementary therapies and conventional medicine. Aromatherapy, one of the complementary therapies, is a centuries-old tradition, used in many cultures and societies as an alternative to, or in conjunction with, conventional medicine. However, there is very little understanding of its therapeutic benefits in the scientific realm related to the correct dosage of essential oils, their delivery mechanism and their efficacy on human physiology in general. We reviewed studies published between 2011–2021 focused on aromatherapy and textiles, and explore “textile” materials as a possible carrier for essential oils in this paper. Due to their proximity to the biggest organ of the human body, textiles can potentially serve as a good delivery system for the therapeutic benefit of essential oils. After this rigorous review, we found gaps in the field. Therefore, we propose cross-disciplinary synergies for future research to fully understand the therapeutic efficacy of essential oils.

Activation of the aryl hydrocarbon receptor by clozapine induces preadipocyte differentiation and contributes to endothelial dysfunction

Background: The superior therapeutic benefit of clozapine is often associated with metabolic disruptions as obesity, insulin resistance, tachycardia, higher blood pressure, and even hypertension. Aims: These adverse vascular/ metabolic events under clozapine are similar to those caused by polycyclic aromatic hydrocarbons (PAHs), and clozapine shows structural similarity to well-known ligands of the aryl hydrocarbon receptor (AhR). Therefore, we speculated that the side effects caused by clozapine might rely on AhR signaling. Methods: We examined clozapine-induced AhR activation by luciferase reporter assays in hepatoma HepG2 cells and we proved upregulation of the prototypical AhR target gene Cyp1A1 by realtime-PCR (RT-PCR) analysis and enzyme activity. Next we studied the physiological role of AhR in clozapine’s effects on human preadipocyte differentiation and on vasodilatation by myography in wild-type and AhR-/- mice. Results: In contrast to other antipsychotic drugs (APDs), clozapine triggered AhR activation and Cyp1A1 expression in HepG2 cells and adipocytes. Clozapine induced adipogenesis via AhR signaling. After PGF2α-induced constriction of mouse aortic rings, clozapine strongly reduced the maximal vasorelaxation under acetylcholine in rings from wild-type mice, but only slightly in rings from AhR-/- mice. The reduction was also prevented by pretreatment with the AhR antagonist CH-223191. Conclusion: Identification of clozapine as a ligand for the AhR opens new perspectives to explain common clozapine therapy-associated adverse effects at the molecular level.

Kidney-Targeted Redox Scavenger Therapy Prevents Cisplatin-Induced Acute Kidney Injury

Cisplatin-induced acute kidney injury (CI-AKI) is a significant co-morbidity of chemotherapeutic regimens. While this condition is associated with substantially lower survival and increased economic burden, there is no pharmacological agent to effectively treat CI-AKI. The disease is hallmarked by acute tubular necrosis of the proximal tubular epithelial cells primarily due to increased oxidative stress. We investigated a drug delivery strategy to improve the pharmacokinetics of an approved therapy that does not normally demonstrate appreciable efficacy in CI-AKI, as a preventive intervention. In prior work, we developed a kidney-selective mesoscale nanoparticle (MNP) that targets the renal proximal tubular epithelium. Here, we found that the nanoparticles target the kidneys in a mouse model of CI-AKI with significant damage. We evaluated MNPs loaded with the reactive oxygen species scavenger edaravone, currently used to treat stroke and ALS. We found a marked and significant therapeutic benefit with edaravone-loaded MNPs, including improved renal function, which we demonstrated was likely due to a decrease in tubular epithelial cell damage and death imparted by the specific delivery of edaravone. The results suggest that renal-selective edaravone delivery holds potential for the prevention of acute kidney injury among patients undergoing cisplatin-based chemotherapy.

HDLs extract lipophilic drugs from cells

High-density lipoproteins (HDLs) prevent cell death induced by a variety of cytotoxic drugs. The underlying mechanisms are however still poorly understood. Here we present evidence that HDLs efficiently protect cells against thapsigargin (TG), a sarco/ endoplasmic reticulum (ER) Ca2+-ATPase (SERCA) inhibitor, by extracting the drug from cells. Drug efflux could also be triggered to some extent by low-density lipoproteins and serum. HDLs did not reverse the non-lethal mild ER stress response induced by low TG concentrations or by SERCA knock-down but HDLs inhibited the toxic SERCA-independent effects mediated by high TG concentrations. HDLs could extract other lipophilic compounds, but not hydrophilic substances This work shows that HDLs utilize their capacity of loading themselves with lipophilic compounds, akin to their ability to extract cellular cholesterol, to reduce the cell content of hydrophobic drugs. This can be beneficial if lipophilic xenobiotics are toxic but may be detrimental to the therapeutic benefit of lipophilic drugs such as glibenclamide.

Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis

The GM2 gangliosidoses Tay-Sachs disease and Sandhoff disease (SD) are respectively caused by mutations in the HEXA and HEXB genes encoding the α and β subunits of β-N-acetylhexosaminidase (Hex). The consequential accumulation of ganglioside in the brain leads to severe and progressive neurological impairment. There are currently no approved therapies to counteract or reverse the effects of GM2 gangliosidosis. Adeno-associated vector (AAV)-based investigational gene therapy (GT) products have raised expectations but come with safety and efficacy issues that need to be addressed. Thus, there is an urgent need to develop novel therapies targeting the CNS and other affected tissues that are appropriately timed to ensure pervasive metabolic correction and counteract disease progression. In this report, we show that the sequential administration of lentiviral vector (LV)-mediated intracerebral (IC) GT and bone marrow transplantation (BMT) in pre-symptomatic SD mice provide a timely and long-lasting source of the Hex enzyme in the central and peripheral nervous systems and peripheral tissues, leading to global rescue of the disease phenotype. Combined therapy showed a clear therapeutic advantage compared to individual treatments in terms of lifespan extension and normalization of the neuroinflammatory and neurodegenerative phenotypes of the SD mice. These benefits correlated with a time-dependent increase in Hex activity and a remarkable reduction in GM2 storage in the brain tissues that single treatments failed to achieve. Our results highlight the complementary and synergic mode of action of LV-mediated IC GT and BMT, clarify the relative contribution of treatments to the therapeutic outcome, and inform on the realistic threshold of enzymatic activity that is required to achieve a significant therapeutic benefit, with important implications for the monitoring and interpretation of ongoing experimental therapies, and for the design of more effective treatment strategies for GM2 gangliosidosis.

Engineered High-Affinity ACE2 Peptide Mitigates ARDS and Death Induced by Multiple SARS-CoV-2 Variants

Vaccine hesitancy and continuing emergence of SARS-CoV-2 variants of concern that may escape vaccine-induced immune responses highlight the urgent need for effective COVID-19 therapeutics. Monoclonal antibodies used in the clinic have varying efficacies against distinct SARS-CoV-2 variants; thus, there is considerable interest in engineered ACE2 peptides with augmented binding affinities for SARS-CoV-2 Spike protein. These could have therapeutic benefit against multiple viral variants. Using machine learning and molecular dynamics simulations, we show how three amino acid substitutions in an engineered soluble ACE2 peptide (sACE22.v2.4-IgG1) markedly increase affinity for the SARS-CoV-2 Spike (S) protein. We demonstrate high binding affinity to S protein of the early SARS-CoV-2 WA-1/2020 isolate and also to multiple variants of concern: B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta) SARS-CoV-2 variants. In humanized K18-hACE2 mice, prophylactic and therapeutic administration of sACE22.v2.4-IgG1 peptide prevented acute lung vascular endothelial injury and lung edema (essential features of ARDS) and significantly improved survival after infection by SARS-CoV-2 WA-1/2020 as well as P.1 variant of concern. These studies demonstrate for the first time broad efficacy in vivo of an ACE2 decoy peptide against multiple SARS-CoV-2 variants and point to its therapeutic potential.