Epigenome Modulation Induced by Ketogenic Diets

Ketogenic diets (KD) are dietary strategies low in carbohydrates, normal in protein, and high, normal, or reduced in fat with or without (Very Low-Calories Ketogenic Diet, VLCKD) a reduced caloric intake. KDs have been shown to be useful in the treatment of obesity, metabolic diseases and related disorders, neurological diseases, and various pathological conditions such as cancer, nonalcoholic liver disease, and chronic pain. Several studies have investigated the intracellular metabolic pathways that contribute to the beneficial effects of these diets. Although epigenetic changes are among the most important determinants of an organism’s ability to adapt to environmental changes, data on the epigenetic changes associated with these dietary pathways are still limited. This review provides an overview of the major epigenetic changes associated with KDs.     

CATSHL syndrome,a new family and phenotypic expansion

We report the case of a 12-year-old girl and her father who both had marked postnatal tall stature, camptodactyly and clinodactyly, scoliosis and juvenile-onset hearing loss. The CATSHL (CAmptodactyly – Tall stature – Scoliosis – Hearing Loss syndrome) syndrome was suspected, and molecular analysis revealed a hitherto unreported, monoallelic variant c.1861C>T (p.Arg621Cys) in FGFR3. This variant affects the same residue, but is different than, the variant p.Arg621His reported in the two families with dominant CATSHL described so far. Interestingly, peg-shaped incisors were observed in the proband, a feature never reported in CATSHL but typical of another FGFR3-related condition, LADD (Lacrimo – Auricolo – Dento – Digital) syndrome. The FGFR3 p.Arg621Cys variant seems to be a newly identified cause of CATSHL syndrome with some phenotypic overlap with the LADD syndrome.     

Perinatal exposure to tributyltin affects feeding behavior and expression of hypothalamic neuropeptide Y in the paraventricular nucleus of adult mice

Organotins such as tributyltin chloride (TBT), are highly diffused environmental pollutants, which act as metabolism disrupting chemicals, i.e. may interfere with fat tissue differentiation, as well as with neuroendocrine circuits, thus impairing the control of energetic balance. We have previously demonstrated that adult exposure to TBT altered the expression of neuropeptides in the hypothalamus. In this study, we orally administered daily a solution containing oil, or TBT (0.25, 2.5, or 25 μg/kg body weight/day) to pregnant females from gestational day 8 until birth, and to their pups from day 0 until post‐natal day 21. Our results showed that TBT exposure of female mice during gestation and of pups during lactation permanently altered the feeding efficiency of pups of both sexes and subcutaneous fat distribution in adult males. In addition, the neuropeptide Y system was affected at the level of the paraventricular nucleus, with a decrease in immunoreactivity in both sexes (significant in females for all TBT doses and in males only for intermediate TBT doses), while no effect was observed in other hypothalamic areas (arcuate, ventromedial and dorsomedial nuclei). Metabolic syndrome, as well as obesity and diabetes, which are significant health issues, are considered multifactorial diseases and may be caused by exposure to metabolic disruptors, both in adults and during perinatal life. In addition, our work indicates that TBT doses defined as the tolerably daily intake had a profound and sex‐specific long‐term effect.     

Chimeric antigen receptor-modified human regulatory T cells that constitutively express IL-10 maintain their phenotype and are potently suppressive

Clinical trials of Treg therapy in transplantation are currently entering phases IIa and IIb, with the majority of these employing polyclonal Treg populations that harbor a broad specificity. Enhancing Treg specificity is possible with the use of chimeric antigen receptors (CARs), which can be customized to respond to a specific human leukocyte antigen (HLA). In this study, we build on our previous work in the development of HLA-A2 CAR-Tregs by further equipping cells with the constitutive expression of interleukin 10 (IL-10) and an imaging reporter as additional payloads. Cells were engineered to express combinations of these domains and assessed for phenotype and function. Cells expressing the full construct maintained a stable phenotype after transduction, were specifically activated by HLA-A2, and suppressed alloresponses potently. The addition of IL-10 provided an additional advantage to suppressive capacity. This study therefore provides an important proof-of-principle for this cell engineering approach for next-generation Treg therapy in transplantation.     

Mesenchymal stromal cell secretome in liver failure: Perspectives on COVID-19 infection treatment

Due to their immunomodulatory potential and release of trophic factors that promote healing, mesenchymal stromal cells (MSCs) are considered important players in tissue homeostasis and regeneration. MSCs have been widely used in clinical trials to treat multiple conditions associated with inflammation and tissue damage. Recent evidence suggests that most of the MSC therapeutic effects are derived from their secretome, including the extracellular vesicles, representing a promising approach in regenerative medicine application to treat organ failure as a result of inflammation/fibrosis. The recent outbreak of respiratory syndrome coronavirus, caused by the newly identified agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has forced scientists worldwide to use all available instruments to fight the infection, including the inflammatory cascade caused by this pandemic disease. The use of MSCs is a valid approach to combat organ inflammation in different compartments. In addition to the lungs, which are considered the main inflammatory target for this virus, other organs are compromised by the infection. In particular, the liver is involved in the inflammatory response to SARS-CoV-2 infection, which causes organ failure, leading to death in coronavirus disease 2019 (COVID-19) patients. We herein summarize the current implications derived from the use of MSCs and their soluble derivatives in COVID-19 treatment, and emphasize the potential of MSC-based therapy in this clinical setting.     

Dietary Patterns,Dietary Interventions,and Mammographic Breast Density: A Systematic Literature Review

Background: Breast cancer (BC) is the most common and deadliest malignancy among women. High mammographic breast density (MBD) is an established modifiable risk marker for BC, and it is of interest, for prevention purposes, to consider lifestyle factors that may modulate both MBD and BC risk. Here, we conducted a systematic review of the most up-to-date evidence on the association between diet as a whole and MBD. Methods: We considered as eligible for inclusion in our review (PROSPERO registration code CRD42022335289) the studies published until 31 December 2021, that reported on the association between a priori or a posteriori dietary patterns (in observational studies) or dietary interventions (in randomized controlled trials) and MBD. Results: In total, twelve studies were included. MBD tended to be inversely associated with adherence to dietary patterns characterized by high consumption of plant-based foods and low in meat, animal fats, and alcohol, defined both a priori (e.g., Mediterranean diet and WCRF/AICR guidelines) or a posteriori (e.g., “fruit-vegetable-cereal” and “salad-sauce-pasta/grains” patterns). Findings from intervention studies were in fair agreement with those from observational studies. Conclusions: While further studies are needed, we found suggestive evidence that the adoption of a healthy diet is associated with lower MBD.     

Erratum to: The conversion rate of tuberculosis screening tests during biological therapies in patients with rheumatoid arthritis

Clinical Rheumatology -     

Well-Being and Perceived Quality of Life in Elderly People Displaced After the Earthquake in L’Aquila,Italy

On 6 April 2009, the city of L’Aquila was hit by a violent earthquake that destroyed almost all of its medieval centre, and the surviving inhabitants were evacuated and relocated in temporary quarters or undamaged homes. The aim of this study was to investigate the perceived quality of life of the elderly population 3 years after the earthquake in relation to the social and logistic issues of new housing. The study was carried out between October 2011 and March 2012, and involved 571 subjects aged over 65 years living in the municipality of L’Aquila. The interviews took place in the surgeries of general practitioners and the city’s Department of Prevention and Vaccination in the anti-influenza immunisation period. The instrument used was a 36-item questionnaire with closed, multiple choice answers divided into the following sections: demographics, everyday activities, health and perceived health, and the quality of life in the city. The results show that, 3 years after the earthquake, the elderly population living in the new towns and temporary housing of L’Aquila have a worse perception of their quality of life than the others. They feel a certain social isolation and wish to live elsewhere. Governments faced with the problems arising from a natural calamity should take into account all of the elements making up a good quality of life and, before making choices whose impact cannot be changed, consider both their immediate and long-term social consequences.