Distinct Glucocorticoid Receptor Actions in Bone Homeostasis and Bone Diseases

Glucocorticoids (GCs) are steroid hormones that respond to stress and the circadian rhythm. Pharmacological GCs are widely used to treat autoimmune and chronic inflammatory diseases despite their adverse effects on bone after long-term therapy. GCs regulate bone homeostasis in a cell-type specific manner, affecting osteoblasts, osteoclasts, and osteocytes. Endogenous physiological and exogenous/excessive GCs act via nuclear receptors, mainly via the GC receptor (GR). Endogenous GCs have anabolic effects on bone mass regulation, while excessive or exogenous GCs can cause detrimental effects on bone. GC-induced osteoporosis (GIO) is a common adverse effect after GC therapy, which increases the risk of fractures. Exogenous GC treatment impairs osteoblastogenesis, survival of the osteoblasts/osteocytes and prolongs the longevity of osteoclasts. Under normal physiological conditions, endogenous GCs are regulated by the circadian rhythm and circadian genes display oscillatory rhythmicity in bone cells. However, exogenous GCs treatment disturbs the circadian rhythm. Recent evidence suggests that the disturbed circadian rhythm by continuous exogenous GCs treatment can in itself hamper bone integrity. GC signaling is also important for fracture healing and rheumatoid arthritis, where crosstalk among several cell types including macrophages and stromal cells is indispensable. This review summarizes the complexity of GC actions via GR in bone cells at cellular and molecular levels, including the effect on circadian rhythmicity, and outlines new therapeutic possibilities for the treatment of their adverse effects.

Mechanism and Protection of Radiotherapy Induced Sensorineural Hearing Loss for Head and Neck Cancer

Purpose. Radiotherapy-induced sensorineural hearing loss (RISNHL) is a common adverse effect in patients with head and neck cancer. Given that there are few studies on the pathogenesis of RISNHL at present, we summarized the possible pathogenesis of RISNHL and possible protective measures found at present by referring to relevant literatures. Methods. We performed a comprehensive literature search in the PubMed database, using keywords “sensorineural hearing loss,” “radiotherapy,” and “cancer,” among others. The literature was examined for the possible mechanism and preventive measures of sensorineural hearing loss induced by radiotherapy. Results. We found that the incidence of RISNHL was closely related to the damage directly caused by ionizing radiation and the radiation-induced bystander effect. It also depends on the dose of radiation and the timing of chemotherapy. Studies confirmed that RISNHL is mainly involved in post-RT inflammatory response and changes in reactive oxygen species, mitogen-activated protein kinase, and p53 signaling pathways, leading to specific manners of cell death. We expect to reduce the incidence of hearing loss through advanced radiotherapy techniques, dose limitation of organs at risk, application of cell signaling inhibitors, use of antioxidants, induction of cochlear hair cell regeneration, and cochlear implantation. Conclusion. RISNHL is associated with radiation damage to DNA, oxidative stress, and inflammation of cochlear cells, stria vascularis endothelial cells, vascular endothelial cells, spiral ganglion neurons, and other supporting cells. At present, the occurrence mechanism of RISNHL has not been clearly illustrated, and further studies are needed to better understand the underlying mechanism, which is crucial to promote the formulation of better strategies and prevent the occurrence of RISNHL.

Good Tumor Response to Chemoradioimmunotherapy in dMMR/MSI-H Advanced Colorectal Cancer: A Case Series

PurposeImmune checkpoint blockade has led to a significant improvement of patient survival in metastatic colorectal cancer (CRC) with DNA mismatch repair-deficiency (dMMR)/microsatellite instability-high (MSI-H). However, not all these patients are sensitive to monoimmunotherapy. We firstly presented a case series of advanced dMMR/MSI-H CRCs treating with PD-1 inhibitor-based chemoradioimmunotherapy (CRIT).Methods and MaterialsWe assessed the short-term efficacy and safety of CRIT in advanced dMMR/MSI-H CRCs, and also did next-generation sequencing (NGS) assays.ResultsOur analysis included five advanced dMMR/MSI-H CRCs who have received toripalimab-based CRIT. Toripalimab was given 240mg every three weeks, and the radiation dose was 45-50 gray in 25 fractions. Chemotherapy regimens consisted of CAPOX in three patients, capecitabine in one patient, and mFOLFOX6 in one patient. Initially, two patients displayed complete response (CR), and three patients achieved partial response (PR) on imaging findings. Afterwards, one PR patient was confirmed pathological complete response after surgery, leading to three CR cases in total. Hematological toxicity was the most common adverse effect, and only two patients developed mild immune-related adverse effects besides. All the treatment-related adverse events were under control. Based on the NGS results, the median intratumor heterogeneity was 0.19 (range 0-0.957), which was less in CR patients than PR patients (P = 0.019). Genetic mutations at DNA damage repair genes and the JAK1 gene were also observed.ConclusionsFor advanced dMMR/MSI-H CRC, anti-PD-1 based CRIT is effective and safe. Further studies are required to better clarify the potential role and mechanism of CRIT as a viable therapeutic strategy in this population.

A study to evaluate the efficacy and safety of intradermal and intralesional Purified Protein Derivative (PPD) for treatment of common warts in children

: Viral warts are common dermatological diseases with wide range of treatment modalities. Utilization of various vaccines and skin test antigens has broadened the horizon of available immunotherapeutic agents for the treatment of warts. In this study, we compared efficacy and safety of intradermal and intralesional purified protein derivative (PPD) for treating common warts in children. Toevaluate efficacy and safety of intradermal and intralesional PPD in treatment of common warts in children.: 180 children (aged 5-15 years) with common warts were randomly divided to receive intradermal (n=90) PPD 10 TU/0.1 ml at middle third of right forearm or intralesional PPD (n=90) 0.1 ml in the largest wart once in 2-weeks till there is complete clearance or maximum of five injections whichever is earlier. Patients were followed at 4 week after last injection for assessment of response, adverse effects, and recurrence of common warts. : Complete, partial clearance and no response in 51.2%, 45.3% and 2.3% children was observed in intradermal group as compared to 54.2%, 42.5% and 1.1% response in intralesional group respectively. Recurrence of warts was observed in 1.2% and 2.2% children in intradermal and intralesional group respectively. Pain was the most common adverse effect in both groups followed by erythema lasting for 2-3 days not warranting for discontinuation of treatment in any patient.: Overall 96.5% and 96.7% patients in both intradermal and intralesional group responded to treatment respectively. We conclude that immunotherapy with PPD appears safe, effective, and acceptable treatment modality for common warts in children. Although intralesional group showed slightly higher efficacy for warts (0.2%), intradermal PPD has advantage of less pain, high patient satisfaction, less spillage of injection material onto surroundings and better compliance over intralesional group and hence can be considered as valuable first line treatment in children in resource poor developing countries.

A worldwide systematic review and meta-analysis of bacteria related to antibiotic-associated diarrhea in hospitalized patients

Introduction Antibiotic-associated diarrhea (AAD) is a major hospital problem and a common adverse effect of antibiotic treatment. The aim of this study was to investigate the prevalence of the most important bacteria that cause AAD in hospitalized patients. Materials and methods PubMed, Web of Science and Scopus databases were searched using multiple relevant keywords and screening carried out based on inclusion/exclusion criteria from March 2001 to October 2021. The random-effects model was used to conduct the meta-analysis. Results Of the 7,377 identified articles, 56 met the inclusion criteria. Pooling all studies, the prevalence of Clostridioides (Clostridium) difficile, Clostridium perfringens, Klebsiella oxytoca, and Staphylococcus aureus as AAD-related bacteria among hospitalized patients were 19.6%, 14.9%, 27%, and 5.2%, respectively. The prevalence of all four bacteria was higher in Europe compared to other continents. The highest resistance of C. difficile was estimated to ciprofloxacin and the lowest resistances were reported to chloramphenicol, vancomycin, and metronidazole. There was no or little data on antibiotic resistance of other bacteria. Conclusions The results of this study emphasize the need for a surveillance program, as well as timely public and hospital health measures in order to control and treat AAD infections.

Efficacy and Safety of Different Formulations of Calcipotriol/Betamethasone Dipropionate in Psoriasis: Gel, Foam, and Ointment

Preparations containing calcipotriol combined with betamethasone dipropionate (in the forms of ointment, gel, and foam) are available for the topical treatment of psoriasis. This review summarizes the differences in the efficacy and safety of these formulations, as well as the preferences of patients with various forms of psoriasis (plaque, scalp, and nail psoriasis). It has been documented that foams provide higher bioavailability, resulting in increased efficacy in plaque psoriasis compared to ointments and gels. Gels or foams are preferred by patients for their different practical qualities (e.g., gels for “easy application”, and foams for “immediate relief”). The available data indicate that ointments may be the most effective formulation in nail psoriasis, and gels are preferred by patients with scalp psoriasis because of their cosmetic features. Treatment with a foam formulation is associated with a lower number of medical appointments compared to treatment with an ointment and with a lower probability of developing indications for systemic treatment. The safety profiles of foams, ointments, and gels are comparable, with the most common adverse effect being pruritus at the application site (in 5.8% of the patients). A long-term proactive maintenance therapy markedly reduces the number of relapses and is likely to close the gap between topical and systemic treatment in psoriasis.

Lithium and preventing chemotherapy-induced peripheral neuropathy in breast cancer patients: a placebo-controlled randomized clinical trial

Background Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of some chemotherapy regimens. Lithium has been suggested for CIPN in some animal studies. We aimed to study lithium’s preventive effect on CIPN in breast cancer patients treated with taxanes and platinum-based medications. Method A double-blind placebo-controlled randomized clinical trial (RCT) was implemented on 36 breast cancer patients in two equal-size groups by block randomization. Participants in both groups consumed daily tablets, either placebo or lithium (300 mg), for 5 days in each course of chemotherapy. The tablets were prescribed 1 day before the start of chemotherapy. The electromyography (EMG) and nerve-conduction-velocity (NCV) tests were achieved before the first chemotherapy, 3 and 9 months after the treatment. The changes and signs or symptoms of CIPN, such as numbness, tingling, freezing, sensitivity to touch, muscle weakness, fibrillation, and knee and elbow reflex disorders, were recorded by examination. The trend of outcome changes was compared between two groups during the 9 months of study. Results In both groups, neurologic signs and symptoms were exacerbated during the first 3 months and improved up to the ninth month of study. Results showed significant changes of all EMG-NCV variables during the 9 months of research in each group (P < 0.001), but the interaction of time and group effect was not significant in none of those indices. All symptoms changed significantly over the study time (P < 0.001) without significant statistical difference between the two groups (P=0.352). No side effect was found during the study. Conclusion The study showed that 300 mg lithium prescription once daily for 5 days might not effectively prevent CIPN in breast cancer patients. Evaluation of lithium effect on CIPN on different cancers in future studies is suggested. Trial registration Iranian Registry of Clinical Trials IRCT20160813029327N10. Registration date: May 16, 2018.

Micropulse Transscleral Cyclophotocoagulation as Primary Surgical Treatment for Primary Open Angle Glaucoma in Taiwan during the COVID-19 Pandemic

Glaucoma is the leading cause of irreversible blindness worldwide, with primary open angle glaucoma (POAG) accounting for the greatest number of total glaucoma cases. This study aimed to evaluate the efficacy and safety of micropulse transscleral cyclophotocoagulation (MP-TSCPC) as a primary procedure in POAG during the COVID-19 pandemic. We retrospectively analyzed 60 eyes of 52 patients, who were diagnosed with mild-to-end-stage POAG without previous glaucoma surgery and received MP-TSCPC between 1 January 2020 and 31 August 2020. The mean preoperative intraocular pressure (IOP) significantly decreased from 27.8 mm Hg to 19.8, 20.1, 20.3, 20.4, and 20.2 mm Hg at 1, 3, 6, 9, and 12 months, respectively (all p < 0.05). The mean number of IOP-lowering medications used significantly decreased from 3.3 at the baseline to 1.6, 1.8, 1.8, 1.9, and 1.9 at 1, 3, 6, 9, and 12 months, respectively (all p < 0.001). Total withdrawal of antiglaucoma medications was fulfilled in five patients. The main outcome was achieved in 81.7% at postoperative month 12. The most common adverse effect was transient mydriasis (28.3%). No major complications were encountered. MP-TSCPC seems to be an effective and safe treatment to reduce IOP and the medication burden with minimal vision-threatening complications in mild-to-end-stage POAG patients without previous glaucoma surgery.

Health Effects of Dyes, Minerals, and Vitamins Used in Cosmetics

The average woman uses 12 different cosmetic products every day, but they can have a negative effect on human health. Therefore, in recent years, consumer preferences have changed towards buying natural or ecological cosmetics free from preservatives or unnecessary dyes. The aim of this work is to discuss the use of dyes, minerals, and vitamins in cosmetics in terms of their safety and impact on human health. These substances are very important in the cosmetics industry. Most of them are of natural origin. Some minerals used in the production of face masks or creams are recommended to work against inflammations such as ulcers and acne. Clay minerals have exceptional qualities, among others, low or no toxicity and high bio-compatibility. However, some of them may be harmful. For example, the safety of using talc has been widely debated in recent years. Cosmetic-grade talc cannot contain detectable fibrous asbestos minerals. Moreover, talc should not be applied to the skin when the epidermal barrier is missing or significantly disrupted. The use of talc in cosmetic products in the European Union is restricted. Vitamins are one of the most commonly used, biologically active, and easily accessible components in cosmetics. For example, provitamin B5 (D-panthenol) is a bioactive substance. In cosmetic preparations, it has a softening, repairing, and anti-inflammatory effect and is responsible for regulating sebum secretion. However, some vitamins may be harmful to human health. For example, the use of skin-whitening cosmetics containing vitamin C causes allergic contact dermatitis, whereas the most common adverse effect of topical use of vitamin A is skin irritation, erythema, and peeling. Dyes, which are used to color cosmetics, do not improve the condition of the skin, hair, or nails. Some of them may be harmful to human health. For example, the dye CI 60730 (Acid Violet 43) is prohibited for use in eye products and cosmetics that have contact with mucous membranes. In conclusion, some of the popular cosmetic ingredients discussed in this paper may exert a negative influence on human health, and many of these harmful effects have been discovered recently. Therefore, there is a need for further studies on the possible negative effects of dyes, minerals, and vitamins used in cosmetic products.

Efficacy of tocilizumab for refractory Takayasu arteritis: a retrospective study and literature review

To evaluate the efficacy and safety of tocilizumab (TCZ) in the treatment of refractory Takayasu arteritis (TAK). Eleven refractory TAK patients treated with TCZ at the First Affiliated Hospital of Anhui Medical University between 2017 July and 2020 December were respectively analyzed. We also respectively analyzed the studies on TCZ efficacy in patients with TAK, from PubMed/MEDLINE, Elsevier Science Direct between January 2010 and April 2021. The median age of 11 patients was 34(19–46) years. After 3 months of TCZ, a significant drop was found in median NIH (3[2–5] at baseline vs 1[0–2] after 6 months; p < 0.05), ITAS-2010 score (8.5[6–11] vs 6[1–10]; p < 0.05). One (9%) patient experienced relapse during TCZ treatment. After withdrawal of TCZ, one patient (9%) underwent relapse and nine patients (81%) were spared of GC use. In literature review, a total of 211 patients (mean age 35 years) were analyzed, including 80 (38%) Chinese and 169 females (80%). Among the 211 patients, (154 patients) 73% achieved remission after the last infusion of TCZ; TAK relapsed in 6% of patients during TCZ treatment and 5% of the TCZ patients after the withdrawal of TCZ. A total of 95 types of adverse events were observed in the literature. Infection was the most common adverse effect, occurring in 50% of patients. TCZ could serve as an efficacious and safe agent for refractory TAK.