Chloroquine decreases cardiac fibrosis and improves cardiac function in a mouse model of Duchenne muscular dystrophy

by Takuya Hirata, Shiro Baba, Kentaro Akagi, Koichi Matsuda, Katsutsugu Umeda, Souichi Adachi, Toshio Heike, Junko Takita

Background

Duchenne muscular dystrophy (DMD), a severe degenerative skeletal and cardiac muscle disease, has a poor prognosis, and no curative treatments are available. Because decreased autophagy has been reported to contribute to skeletal muscle degeneration, therapies targeting autophagy are expected to improve skeletal muscle hypofunction. However, the role of this regulatory mechanism has not been evaluated clearly in DMD cardiomyocytes.

Methods

In this present study, we evaluated myocardial fibrosis and its mechanism in mdx mice, a model of DMD, and also evaluated changes in cardiac function.

Results

As assessed by LC3 immunohistochemistry, a small number of autophagosomes were detected in cardiomyocytes of both mdx mice and control wild-type (WT) mice. The number of autophagosomes was significantly enhanced by 4 weeks of isoproterenol-induced cardiac stress in cardiomyocytes of mdx but not WT mice. Simultaneously, isoproterenol increased cardiomyocyte fibrosis in mdx but not WT mice. Administration of chloroquine significantly decreased cardiomyocyte fibrosis in mdx mice, even after isoproterenol treatment. Left ventricle size and function were evaluated by echocardiography. Left ventricular contraction was decreased in mdx mice after isoproterenol treatment compared with control mice, which was alleviated by chloroquine administration.

Conclusions

Heart failure in DMD patients is possibly treated with chloroquine, and the mechanism probably involves chloroquine’s anti-inflammatory effects.

Dexamethasone restores TNFα-induced epithelial barrier dysfunction in primary rat alveolar epithelial cells

by Naokata Kutsuzawa, Yoko Ito, Shizuko Kagawa, Chinatsu Kohno, Hiroto Takiguchi, Koichiro Asano

Alveolar barrier dysfunction is one of the major pathophysiological changes in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). In ALI/ARDS, tumor necrosis factor-alpha (TNFα) disrupts the barriers of alveolar epithelium and endothelium. Glucocorticoids (GCs) exert anti-inflammatory effects and ameliorate pulmonary edema in ALI/ARDS. However, the involvement of GCs in the restoration of alveolar epithelial barrier dysfunction has not been extensively studied. Here, we elucidated that dexamethasone (Dex) restored TNFα-induced alveolar epithelial barrier dysfunction in vitro using primary rat alveolar epithelial cells isolated from Sprague–Dawley rats. Moreover, Dex promoted the alveolar epithelial cell barrier integrity by initiating GC receptor-mediated signaling via the downregulation of myosin light chain kinase (MLCK) expression and the dephosphorylation of myosin light chain (MLC) 2. Further investigation revealed that Dex enhanced the expression of zonula occludens-1 (ZO-1), a tight junction-related protein, at intercellular junction sites. These findings suggest that GCs strengthen the integrity of the alveolar epithelial barrier in ALI/ARDS via the GR-MLCK-pMLC2 axis.

"I thought I was going to die": Experiences of COVID-19 patients managed at home in Uganda

by Susan Nakireka, David Mukunya, Crescent Tumuhaise, Ronald Olum, Edith Namulema, Agnes Napyo, Quraish Serwanja, Prossie Merab Ingabire, Asad Muyinda, Felix Bongomin, Milton Musaba, Vivian Mutaki, Ritah Nantale, Phillip Akunguru, Rozen Ainembabazi, Derrick Nomujuni, William Olwit, Aisha Nakawunde, Specioza Nyiramugisha, Pamela Mwa Aol, Joseph Rujumba, Ian Munabi, Sarah Kiguli

Background

In Uganda, approximately 170,000 confirmed COVID-19 cases and 3,630 deaths have been reported as of January 2023. At the start of the second COVID-19 wave, the Ugandan health system was overwhelmed with a sudden increase in the number of COVID-19 patients who needed care, and the Ministry of Health resorted to home-based isolation and care for patients with mild to moderate disease. Before its rollout, the COVID-19 home-based care strategy had neither been piloted nor tested in Uganda.

Objective

To explore the experiences of COVID-19 patients managed at home in Uganda.

Methods

This was a qualitative study that was conducted to explore the lived experiences of COVID-19 patients managed at home. The study was carried out among patients who presented to three hospitals that were designated for treating COVID-19 patients in Uganda. COVID-19 patients diagnosed at these hospitals and managed at home were followed up and contacted for in-depth telephone interviews. The data were analysed using thematic content analysis with the aid of NVIVO 12.0.0 (QRS International, Cambridge, MA).

Results

Participants experienced feelings of fear and anxiety: fear of death, fear of losing jobs, fear of infecting loved ones and fear of adverse events such as loss of libido. Participants also reported feelings of loneliness, hopelessness and depression on top of the debilitating and sometimes worsening symptoms. In addition to conventional medicines, participants took various kinds of home remedies and herbal concoctions to alleviate their symptoms. Furthermore, COVID-19 care resulted in a high economic burden, which persisted after the COVID-19 illness. Stigma was a major theme reported by participants. Participants recommended that COVID-19 care should include counselling before testing and during and after the illness to combat the fear and stigma associated with the diagnosis. Another recommendation was that health workers should carry out home visits to patients undergoing home-based care and that COVID-19 treatment should be free of charge.

Conclusion

COVID-19 home-based care was associated with fear, anxiety, loneliness, depression, economic loss and stigma. Policymakers should consider various home-based follow-up strategies and strengthen counselling of COVID-19 patients at all stages of care.