The human interleukin IL-6 was originally cloned in 1986. In 1993, William Ershler, in his article “IL-6: A Cytokine for Gerontologists,” indicated IL-6 as one of the main signaling pathways ...modulating the complex relationship between aging and chronic morbidity. Over the last 12 years, our understanding of the role of IL-6 in human physiology and pathology has substantially grown, although some of the questions originally posed by Ershler are still debated. In this review, we will focus on IL-6 structure, IL-6 signaling, and trans signaling pathways, and the role of IL-6 in geriatric syndromes and chronic disease. In the final section of this review, we dissect the critical elements of the IL-6 signaling pathway and point out targets for intervention that are targeted by emerging drugs, some still on the horizon and others already being tested in clinical trials.
Immune responses to both SARS-CoV-2 infection and its associated vaccines have been highly variable within the general population. The increasing evidence of long-lasting symptoms after resolution of ...infection, called post-acute sequelae of COVID-19 (PASC) or "Long COVID," suggests that immune-mediated mechanisms are at play. Closely related endemic common human coronaviruses (hCoV) can induce pre-existing and potentially cross-reactive immunity, which can then affect primary SARS-CoV-2 infection, as well as vaccination responses. The influence of pre-existing immunity from these hCoVs, as well as responses generated from original CoV2 strains or vaccines on the development of new high-affinity responses to CoV2 antigenic viral variants, needs to be better understood given the need for continuous vaccine adaptation and application in the population. Due in part to thymic involution, normal aging is associated with reduced naïve T cell compartments and impaired primary antigen responsiveness, resulting in a reliance on the pre-existing cross-reactive memory cell pool which may be of lower affinity, restricted in diversity, or of shorter duration. These effects can also be mediated by the presence of down-regulatory anti-idiotype responses which also increase in aging. Given the tremendous heterogeneity of clinical data, utilization of preclinical models offers the greatest ability to assess immune responses under a controlled setting. These models should now involve prior antigen/viral exposure combined with incorporation of modifying factors such as age on immune responses and effects. This will also allow for mechanistic dissection and understanding of the different immune pathways involved in both SARS-CoV-2 pathogen and potential vaccine responses over time and how pre-existing memory responses, including potential anti-idiotype responses, can affect efficacy as well as potential off-target effects in different tissues as well as modeling PASC.
The editors of the
Journal
note that although the rapid development of Covid-19 vaccines would appear to be a landmark success in global health mobilization, the truth is very different: the ...availability of the vaccines differs vastly across the globe.
In July 2018, the
Journal
published the results of TAILORx (Trial Assigning Individualized Options for Treatment).
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This randomized trial conducted by Sparano et al. showed the noninferiority of ...endocrine therapy to chemoendocrine therapy with respect to invasive disease–free survival among women with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer who had a recurrence score (based on a 21-gene assay) of 11 to 25 (scores range from 0 to 100, with higher scores predicting a higher risk of distant recurrence). This was the primary objective of the trial; interactions on the multiplicative scale between randomized treatment . . .
Treatment for patients with Hodgkin’s lymphoma is one of the success stories of modern medicine. A once uniformly fatal disorder is now curable, even in an advanced stage, in the great majority of ...patients. In fact, particularly in limited-stage Hodgkin’s lymphoma, much of the therapeutic focus is on maintaining the high probability of cure while reducing the incidence of toxic effects. How little therapy can we give without losing efficacy? For patients with advanced-stage, high-risk disease, debates regarding the best currently available approach have centered on the “old standard” ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) regimen,
1
the very intensive escalated . . .
Telomeres are essential in maintaining chromosome integrity and in controlling cellular replication. Attrition of telomere length in peripheral blood mononuclear cells (PBMCs) with age is well ...documented from cross-sectional studies. But the actual in vivo changes in telomere lengths and its relationship with the contributing factors within the individuals with age have not been fully addressed. In the present paper, we report a longitudinal analysis of telomere length in the PBMCs, lymphocytes and monocytes of 216 human subjects aged from 20-90 years assessed at 0-, 5- and 12-year follow-up. For the 5- and 12-year follow-up, telomere length in the PBMCs decreased in 34% and 46%, exhibited no detectable change in 56% and 47% and increased in 10% and 7% of the subjects respectively. The rate of telomere change was distinct for T-cells, B-cells and monocytes for any given subject. Telomerase activity declined with age in the resting T-cells and B-cells and the activated T-cells. Finally, a significant portion of telomere attrition in T-cells with age was explained by a decline in the telomerase activity, decreased naïve cells and the change in physiological conditions such as elevated blood glucose and interleukin (IL)-6 levels. These findings show that changes in the telomere length of the PBMCs with age in vivo occur at different rates in different individuals and cell types and reveal that changes in the telomere length in the T-cells with age is influenced by the telomerase activity, naïve T-cell percentage and changes in health conditions.
Long-term use of benzodiazepines can lead to dependence. Symptoms of withdrawal include anxiety, irritability, confusion, seizures, and sleep disorders. Withdrawal management relies on the use of a ...single agent (diazepam) and gradual dose reduction.
Traditionally, various terms have been used to define substance use–related disorders. These include “addiction,” “misuse” (in the
Diagnostic and Statistical Manual of Mental Disorders,
fourth edition DSM-IV
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), “harmful use” (in the
International Classification of Diseases, 10th Revision
ICD-10
2
), and “dependence.”
3
Long-term intake of a drug can induce tolerance of the drug’s effects (i.e., increased amounts are needed to achieve intoxication, or the person experiences diminished effects with continued use
4
) and physical dependence. Addiction is defined by compulsive drug-seeking behavior or an intense desire to take a drug despite severe medical or social consequences. The DSM-IV and ICD-10 . . .
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