'Distant socializing,' not 'social distancing' as a public health strategy for COVID-19.

Social distancing, also referred to as physical distancing, means creating a safe distance of at least two meters (six feet) between yourself and others. This is a term popularized during the COVID-19 pandemic, as it is one of the most important measures to prevent the spread of this virus. However, the term 'social distancing' can be misleading, as it may imply that individuals should stop socializing. However, socializing in a safe context (i.e. over the phone, video-chat, etc.) is especially important during this time of crisis. Therefore, in this narrative review, we suggest the term 'distant socializing' as more apt expression, to promote physical distancing measures while also highlighting the importance of maintaining social bonds. Further, articles discussing the practice, implementation, measurement, and mental health effects of physical distancing are reviewed. Physical distancing is associated with psychiatric symptoms (such as anxiety and depression), suicidal ideation, and domestic violence. Further, unemployment and job insecurity have significantly increased during COVID-19, which may exacerbate these negative mental health effects. Governments, medical institutions, and public health bodies should therefore consider increasing mental health resources both during and after the pandemic, with a specific focus on frontline workers, COVID-19 survivors, and marginalized communities.

Melatonin, environmental light, and breast cancer.

Although many factors have been suggested as causes for breast cancer, the increased incidence of the disease seen in women working in night shifts led to the hypothesis that the suppression of melatonin by light or melatonin deficiency plays a major role in cancer development. Studies on the 7,12-dimethylbenz[a]anthracene and N-methyl-N-nitrosourea experimental models of human breast cancer indicate that melatonin is effective in reducing cancer development. In vitro studies in MCF-7 human breast cancer cell line have shown that melatonin exerts its anticarcinogenic actions through a variety of mechanisms, and that it is most effective in estrogen receptor (ER) alpha-positive breast cancer cells. Melatonin suppresses ER gene, modulates several estrogen dependent regulatory proteins and pro-oncogenes, inhibits cell proliferation, and impairs the metastatic capacity of MCF-7 human breast cancer cells. The anticarcinogenic action on MCF-7 cells has been demonstrated at the physiological concentrations of melatonin attained at night, suggesting thereby that melatonin acts like an endogenous antiestrogen. Melatonin also decreases the formation of estrogens from androgens via aromatase inhibition. Circulating melatonin levels are abnormally low in ER-positive breast cancer patients thereby supporting the melatonin hypothesis for breast cancer in shift working women. It has been postulated that enhanced endogenous melatonin secretion is responsible for the beneficial effects of meditation as a form of psychosocial intervention that helps breast cancer patients.

Melatonin: Nature's most versatile biological signal?

Melatonin is a ubiquitous molecule and widely distributed in nature, with functional activity occurring in unicellular organisms, plants, fungi and animals. In most vertebrates, including humans, melatonin is synthesized primarily in the pineal gland and is regulated by the environmental light/dark cycle via the suprachiasmatic nucleus. Pinealocytes function as 'neuroendocrine transducers' to secrete melatonin during the dark phase of the light/dark cycle and, consequently, melatonin is often called the 'hormone of darkness'. Melatonin is principally secreted at night and is centrally involved in sleep regulation, as well as in a number of other cyclical bodily activities. Melatonin is exclusively involved in signaling the 'time of day' and 'time of year' (hence considered to help both clock and calendar functions) to all tissues and is thus considered to be the body's chronological pacemaker or 'Zeitgeber'. Synthesis of melatonin also occurs in other areas of the body, including the retina, the gastrointestinal tract, skin, bone marrow and in lymphocytes, from which it may influence other physiological functions through paracrine signaling. Melatonin has also been extracted from the seeds and leaves of a number of plants and its concentration in some of this material is several orders of magnitude higher than its night-time plasma value in humans. Melatonin participates in diverse physiological functions. In addition to its timekeeping functions, melatonin is an effective antioxidant which scavenges free radicals and up-regulates several antioxidant enzymes. It also has a strong antiapoptotic signaling function, an effect which it exerts even during ischemia. Melatonin's cytoprotective properties have practical implications in the treatment of neurodegenerative diseases. Melatonin also has immune-enhancing and oncostatic properties. Its 'chronobiotic' properties have been shown to have value in treating various circadian rhythm sleep disorders, such as jet lag or shift-work sleep disorder. Melatonin acting as an 'internal sleep facilitator' promotes sleep, and melatonin's sleep-facilitating properties have been found to be useful for treating insomnia symptoms in elderly and depressive patients. A recently introduced melatonin analog, agomelatine, is also efficient for the treatment of major depressive disorder and bipolar affective disorder. Melatonin's role as a 'photoperiodic molecule' in seasonal reproduction has been established in photoperiodic species, although its regulatory influence in humans remains under investigation. Taken together, this evidence implicates melatonin in a broad range of effects with a significant regulatory influence over many of the body's physiological functions.

Melatonin, immune function and aging.

Aging is associated with a decline in immune function (immunosenescence), a situation known to correlate with increased incidence of cancer, infectious and degenerative diseases. Innate, cellular and humoral immunity all exhibit increased deterioration with age. A decrease in functional competence of individual natural killer (NK) cells is found with advancing age. Macrophages and granulocytes show functional decline in aging as evidenced by their diminished phagocytic activity and impairment of superoxide generation. There is also marked shift in cytokine profile as age advances, e.g., CD3+ and CD4+ cells decline in number whereas CD8+ cells increase in elderly individuals. A decline in organ specific antibodies occurs causing reduced humoral responsiveness. Circulating melatonin decreases with age and in recent years much interest has been focused on its immunomodulatory effect. Melatonin stimulates the production of progenitor cells for granulocytes-macrophages. It also stimulates the production of NK cells and CD4+ cells and inhibits CD8+ cells. The production and release of various cytokines from NK cells and T-helper lymphocytes also are enhanced by melatonin. Melatonin presumably regulates immune function by acting on the immune-opioid network, by affecting G protein-cAMP signal pathway and by regulating intracellular glutathione levels. Melatonin has the potential therapeutic value to enhance immune function in aged individuals and in patients in an immunocompromised state.

Circadian melatonin and cortisol levels in rheumatoid arthritis patients in winter time: a north and south Europe comparison.

BACKGROUND: Altered functioning of the hypothalamic-pituitary-adrenal axis and altered melatonin production might modulate the circadian symptoms in patients with rheumatoid arthritis. OBJECTIVE: To investigate the influence of different winter photoperiods on the circadian rhythms of serum melatonin, cortisol, tumour necrosis factor alpha (TNFalpha), and interleukin 6 (IL6) in patients with rheumatoid arthritis from a north Europe country (Estonia) and a south Europe country (Italy). METHODS: The patients from Estonia (n = 19) and Italy (n = 7) had similar disease severity and duration and were compared with healthy age and sex matched controls in the two countries. Blood samples were collected during the period January to February at 8 pm, 10 pm, midnight, 2 am, 4 am, 6 am, 8 am, and 3 pm. Melatonin was measured by radioimmunoassay using (125)I-melatonin. Serum cortisol, TNFalpha, and IL6 cytokines were assayed by standard methods. RESULTS: Higher circadian melatonin concentrations from 10 pm and an earlier peak were observed in Estonian patients than in their age and sex matched controls (p<0.01). Starting from midnight, melatonin concentrations were significantly higher in the Estonian patients than in the Italian patients. No significant differences were observed for serum cortisol. Serum TNFalpha was higher (p<0.05) in Estonian patients than in their controls and was correlated with the melatonin levels. CONCLUSIONS: In a north European country (Estonia), the circadian rhythm of serum concentrations of melatonin and TNFalpha in patients with rheumatoid arthritis were significantly higher than in matched controls or in rheumatoid patients from a south Europe country (Italy).

Melatonin serum levels in rheumatoid arthritis.

The pineal hormone melatonin (MLT) exerts a variety of effects on the immune system. MLT activates immune cells and enhances inflammatory cytokine and nitric oxide production. Cytokines are strongly involved in the synovial immune and inflammatory response in rheumatoid arthritis (RA) and reach the peak of concentration in the early morning, when MLT serum level is higher. Nocturnal MLT serum levels were evaluated in 10 RA patients and in 6 healthy controls. Blood samples were obtained at 8 and 12 p.m., as well as at 2, 4, 6, and 8 a.m. MLT serum levels at 8 p.m. and 8 a.m. were found to be higher in RA patients than in controls (p < 0.05). In both RA patients and healthy subjects, MLT progressively increased from 8 p.m. to the first hours of the morning, when the peak level was reached (p < 0.02). However, MLT serum level reached the peak at least two hours before in RA patients than in controls (p < 0.05). Subsequently, in RA patients, MLT concentration showed a plateau level lasting two to three hours, an effect not observed in healthy controls. After 2 a.m., MLT levels decreased similarly in both RA patients and healthy subjects. Several clinical symptoms of RA, such as morning gelling, stiffness, and swelling, which are more evident in the early morning, might be related to the neuroimmunomodulatory effects exerted by MLT on synovitis and might be explained by the imbalance between cortisol serum levels (lower in RA patients) and MLT serum levels (higher in RA patients).

A review on cancer--psychospiritual status interactions.

With the advances in the knowledge of neuroimmunomodulation, a new era of investigations about the chemical basis of the state of mind has been initiated. Both emotions and states of spiritual consciousness may influence immune functions and cancer growth. Stress, anxiety and depressive states are associated with immunosuppression and enhanced frequency of tumors. On the other hand, the states of sexual pleasure and spiritual joy enhance the immune efficacy, by counteracting tumor onset and dissemination. The biochemistry of pleasure and immunostimulation is mainly mediated by pineal indoles and cannabinergic substances, whereas that of stress, anxiety and depression is associated with enhanced production of adrenal steroids, opioids and catecholamines. The sexual repression would allow a progressive immunosuppression through a profound damage in the biochemistry of pleasure. Therefore, a better definition of psychospiritual status-associated neuroimmunochemistry could allow us to improve the immune dysfunction by acting on the same neuroendocrine secretions which are involved in mediating the psychic influence on the immunity, including that against cancer.

Efficacy of monochemotherapy with docetaxel (taxotere) in relation to prolactin secretion in heavily pretreated metastatic breast cancer.

OBJECTIVES: Recent data have suggested that the efficacy of cancer chemotherapy does not depend only on tumor-related characteristics, but also on patient biological status, namely immune and endocrine functions. In particular, it has been shown that prolactin (PRL) is a growth factor for breast cancer, and abnormally high blood levels of PRL have been described in metastatic breast cancer patients. The present study was performed to evaluate the efficacy of chemotherapy with taxanes in relation to PRL blood levels in metastatic breast cancer. MATERIAL & METHODS: The study included 20 metastatic breast cancer patients, who were treated with taxotere (100 mg/mq I.V. every 21 days) for at least 3 consecutive cycles. Serum levels of PRL were measured by RIA before the onset of treatment and at 21-days intervals. RESULTS: The clinical response consisted of partial response (PR) in 6, stable disease (SD) in 7 and progressive disease (PD) in the remaining 7 patients. Abnormally high pre-treatment levels of PRL were seen in 7/20 patients. The percent of patients who had PD in response to chemotherapy was significantly high in patients with pre-treatment hyperprolactinemia than in those with normal blood levels of PRL before therapy. CONCLUSIONS: This study shows that the evidence of abnormally high serum levels of PRL correlates with resistance to chemotherapy with taxanes in metastatic breast cancer. Therefore, a concomitant administration of anti-prolactinemic agents, such as bromocriptine, could enhance the efficacy of chemotherapy itself.

Anti-angiogenic activity of melatonin in advanced cancer patients.

OBJECTIVES: The anticancer activity of the indole melatonin has been explained to be due to its immunomodulatory, anti-prolferative and anti-oxidant effects, whereas at present no data are available about its possible influence on the angiogenesis, which has been shown to be one of the main biological mechanisms responsible for tumor dissemination. Vascular endothelial growth factor (VEGF) is the most active angiogenic factor, and the evidence of abnormally high blood levels or VEGF has been proven to be associated with poor prognosis in cancer patients. To investigate the influence of melatonin on angiogenesis, in this preliminary study we have evaluated the effects of melatonin therapy on VEGF blood levels in advanced cancer patients. MATERIAL & METHODS: The study included 20 metastatic patients, who progressed on previous conventional antitumor therapies and for whom no other effective treatment was available. Melatonin was given orally at 20 mg/day in the evening for at least 2 months. Serum levels of VEGF were measured by an enzyme immunoassay on venous blood samples collected at 15-day intervals. RESULTS: The clinical response consisted of minor response (MR) in 2, stable disease (SD) in 6 and progressive disease (PD) in the remaining 12 patients. VEGF mean levels decreased on therapy, without, however, statistical differences with respect to the pre-treatment values. In contrast, by evaluating changes in VEGF levels in relation to the clinical response, non-progressing patients (MR + SD) showed a significant decline in VEGF mean concentrations, whereas no effect was achieved in progressing patients. CONCLUSIONS: This study, by showing that melatonin-induced control or the neoplastic growth is associated with a decline in VEGF secretion, would suggest that the pineal hormone may control tumor growth at least in part by acting as a natural anti-angiogenic molecule, with a following opposition or angiogenesis-dependent cancer proliferation.

The immunotherapeutic potential of melatonin.

The interaction between the brain and the immune system is essential for the adaptive response of an organism against environmental challenges. In this context, the pineal neurohormone melatonin (MEL) plays an important role. T-helper cells express G-protein coupled cell membrane MEL receptors and, perhaps, MEL nuclear receptors. Activation of MEL receptors enhances the release of T-helper cell Type 1 (Th1) cytokines, such as gamma-interferon (gamma-IFN) and IL-2, as well as of novel opioid cytokines. MEL has been reported also to enhance the production of IL-1, IL-6 and IL-12 in human monocytes. These mediators may counteract stress-induced immunodepression and other secondary immunodeficiencies and protect mice against lethal viral encephalitis, bacterial diseases and septic shock. Therefore, MEL has interesting immunotherapeutic potential in both viral and bacterial infections. MEL may also influence haemopoiesis either by stimulating haemopoietic cytokines, including opioids, or by directly affecting specific progenitor cells such as pre-B cells, monocytes and NK cells. MEL may thus be used to stimulate the immune response during viral and bacterial infections as well as to strengthen the immune reactivity as a prophylactic procedure. In both mice and cancer patients, the haemopoietic effect of MEL may diminish the toxicity associated with common chemotherapeutic protocols. Through its pro-inflammatory action, MEL may play an adverse role in autoimmune diseases. Rheumatoid arthritis patients have increased nocturnal plasma levels of MEL and their synovial macrophages respond to MEL with an increased production of IL-12 and nitric oxide (NO). In these patients, inhibition of MEL synthesis or use of MEL antagonists might have a therapeutic effect. In other diseases such as multiple sclerosis the role of MEL is controversial. However, the correct therapeutic use of MEL or MEL antagonists should be based on a complete understanding of their mechanism of action. It is not yet clear whether MEL acts only on Th1 cells or also on T-helper Type 2 cells (Th2). This is an important point as the Th1/Th2 balance is of crucial importance in the immune system homeostasis. Furthermore, MEL being the endocrine messenger of darkness, its endogenous synthesis depends on the photoperiod and shows seasonal variations. Similarly, the pharmacological effects of MEL might also be season-dependent. No information is available concerning this point. Therefore, studies are needed to investigate whether the immunotherapeutic effect of MEL changes with the alternating seasons.

Dendritic cell migration controlled by alpha 1b-adrenergic receptors.

Dendritic cells (DC) bring Ags into lymphoid organs via lymphatic vessels. In this study, we investigated the possibility that the sympathetic neurotransmitter norepinephrine (NE) influences DC migration. Murine epidermal Langerhans cells mobilization is enhanced by systemic treatment with the alpha(2)-adrenergic antagonist yohimbine and inhibited by local treatment with the specific alpha(1)-adrenergic antagonist prazosin (PRA). Consistently, NE enhances spontaneous emigration of DC from ear skin explants, and PRA inhibits this effect. In addition, local treatment with PRA during sensitization with FITC inhibits the contact hypersensitivity response 6 days later. In vitro, bone marrow-derived immature, but not CD40-stimulated mature DC migrate in response to NE, and this effect is neutralized by PRA. NE seems to exert both a chemotactic and chemokinetic activity on immature DC. Coherently, immature, but not mature DC, express mRNA coding for the alpha(1b)-adrenergic receptor subtype. Inactivation of this adrenergic receptor by the specific and irreversible antagonist chloroethylclonidine hinders the migration of injected DC from the footpad to regional lymph nodes. Thus, besides regulating lymph flow, the sympathetic innervation of lymphatic vessels may participate in directing DC migration from the site of inflammation to regional lymph nodes. Alternatively, the chemokinetic activity of NE may enhance the ability of DC to sample local Ags, and hence increase the number of DC migrating to the draining lymph nodes. This finding might improve our understanding of the biological basis of skin diseases and allergic reactions, and opens new pharmacological possibilities to modulate the immune response.

HPLC-ED measurement of endogenous catecholamines in human immune cells and hematopoietic cell lines.

A rapid and simple HPLC-ED method is described to identify and measure catecholamines (CTs) and their major metabolites in immune cells. Using this method, intracellular CTs were quantified in human peripheral blood mononuclear cells (PBMCs), T and B lymphocytes, monocytes and granulocytes. Immune cell subsets were separated by density gradient centrifugation and immunomagnetic cell sorting. CTs were also found in the human hematopoietic cell lines NALM-6 (pre-B) and (in smaller amounts) in Jurkat (T lymphoblastoid) and U937 (promonocytic). In cultured PBMCs, intracellular CTs were reduced by both the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine and the chromaffin granule depletant reserpine. In NALM-6 cells, both alpha-methyl-p-tyrosine and the dopamine-beta-hydroxylase inhibitor disulfiram reduced intracellular CTs, supporting the presence of active synthetic pathways in these cells. Since sympathoadrenergic mechanisms play a key role in the interactions between the immune system and the nervous system, these findings may be relevant for a better understanding of the neuro-immune network.

Neurohormones and catecholamines as functional components of the bone marrow microenvironment.

A variety of cytokines and growth factors exert a finely tuned control on the complex series of proliferative and differentiative events called hematopoiesis. Recent studies have shown that neuroendocrine and neural factors may also regulate hematopoiesis. In particular, besides its important immunoenhancing properties, the pineal neurohormone melatonin can also rescue hematopoiesis from the toxic effect of anti-cancer drugs via the action of T-helper cell novel opioid cytokines. In turn, these substances bind kappa-opioid receptors expressed in GM-CSF-activated macrophage-like stromal cells and seem to stimulate IL-1. Adrenergic agents can also affect hematopoiesis. We demonstrated that pre-B cells express alpha 1B-adrenoceptors (alpha 1B-AR) and that their activation by catecholamines results in suppressed myelopoiesis in vitro or protection in vivo against supralethal doses of carboplatin. Most recently, we found that alpha 1B-AR gene knockout mice show a deranged hematopoietic recovery after sublethal irradiation. Regeneration of pre-B cells (the cell type expressing alpha 1B-AR) and of erythrocytes was much faster in knockout than in wild-type mice. Most interesting, bone marrow cells can synthesize both melatonin and catecholamines. As far as melatonin is concerned, human and murine bone marrow cells contain and synthesize melatonin at a concentration that is three orders of magnitude higher than that normally found in serum. Catecholamines are also present in substantial amounts and originate both from nerve endings and bone marrow cells. These findings open interesting new perspectives and include hematology among the disciplines that would benefit from the integrative NIM approach.

Hematopoietic effect of melatonin involvement of type 1 kappa-opioid receptor on bone marrow macrophages and interleukin-1.

Melatonin has immuno-enhancing properties and exerts colony-stimulating activity (CSA) via T-helper cell-derived opioids. Opioid agonists may mimic the CSA of melatonin with an order of potency that suggests the presence of a type 1 kappa-opioid receptor (type 1 kappaOR [kappa]-OR]). The kappaOR antagonist nor-binaltorphimine neutralized the in vitro effect of melatonin and inhibited regeneration of hematopoiesis in mice treated with carboplatin. The CSA of dynorphin A was abolished by incubation of adherent cells with antisense (AS) oligodeoxynucleotide to kappaOR or by addition of anti-interleukin (IL)-1 monoclonal antibody (mAb), which also neutralized the effect of melatonin. Bone marrow cells that express kappaORs were identified to be macrophages. In conclusion, we describe the presence of kappaORs in bone marrow macrophages and suggest a hematopoietic function for melatonin via endogenous kappa-opioid agonists and, possibly, IL-1.

Factor(s) from nonmacrophage bone marrow stromal cells inhibit Lewis lung carcinoma and B16 melanoma growth in mice.

Bone marrow stroma produces positive and negative growth regulators which constitute the hematopoietic microenvironment. As many tumors metastasize to the bones, these regulators may also influence tumor growth. Hematopoietic cytokines may indeed exert both positive and negative effect on tumor growth. We report that, when mixed with tumor cells. adherent bone marrow cells inhibit primary tumor growth and metastases formation in mice transplanted with Lewis lung carcinoma or B16 melanoma. Peritoneal macrophages or lymph node cells did not exert any influence. The tumor inhibition was apparently due to soluble factor(s) released by marrow stromal cells. In cocultures with B16 melanoma cells, adherent bone marrow cells exerted a significant antiproliferative effect which was increased by previous culture of the bone marrow cells with granulocyte-macrophage colony-stimulating factor but not with macrophage colony-stimulating factor. Neither neutralizing antibodies against tumor necrosis factor-alpha, transforming growth factor-beta or interferon alpha/beta nor addition of Escherichia coli lipopolysaccharide to generate inflammatory cytokines could affect the antiproliferative effect of bone marrow stromal cells. The bone marrow stroma factor(s) which inhibit tumor growth might, therefore, be a novel growth regulator.

Melatonin in relation to the antioxidative defense and immune systems: possible implications for cell and organ transplantation.

Melatonin, a molecule synthesized and secreted by the mammalian (including human) pineal gland, has a variety of seemingly unrelated functions in organisms. In photoperiodically-dependent seasonal breeders, the changing melatonin signal imparts seasonal information to the species thereby regulating the annual cycle of reproduction Melatonin also is involved in a number of 24 h rhythms and is believed to be an important component of the circadian system. More recently, melatonin was found to relate to immune function in organisms and to be an effective antioxidant. As an antioxidant melatonin would appear to provide substantial protection against free radicals which are generated under a variety of experimental corrections, including ischemia/reperfusion injury. These latter two functions of melatonin, i.e., as an immune system modulator and as an antioxidant, both may have applicability to cell and organ transplantation.

Therapeutic potential of melatonin in immunodeficiency states, viral diseases, and cancer.

Maintenance of health depends on the ability to respond appropriately to environmental stressors via reciprocal interactions between the body and the brain. In this context, it is well recognized that the pineal hormone melatonin (MLT) plays an important role. T-helper cells bear G-protein-coupled MLT cell membrane receptors and, perhaps, MLT nuclear receptors. Activation of MLT receptors enhances the release of T-helper cell cytokines, such as gamma-interferon and interleukin-2 (IL-2), as well as activation of novel opioid cytokines which crossreact immunologically with both interleukin-4 and dynorphin B. MLT has been reported also to enhance the production of interleukin-1, interleukin-6 and interleukin-12 in human monocytes. These mediators may counteract secondary immunodeficiencies, protect mice against lethal viral and bacterial diseases, synergize with IL-2 against cancer and influence hematopoiesis. Hematopoiesis is influenced by MLT-induced-opioids (MIO) acting on kappa 1-opioid receptors present on bone marrow macrophages. Clinically, MLT could amplify the anti-tumoral activity of low dose IL-2, induce objective tumor regression, and prolong progression-free time and overall survival. MLT seems to be required for the effectiveness of low dose IL-2 in those neoplasias that are generally resistant to IL-2 alone. Similar findings were obtained in a study in which MLT was combined with gamma-interferon in metastatic renal cell carcinoma. In addition, MLT in combination with low-dose IL-2 was able to neutralize the surgery-induced lymphocytopenia in cancer patients. IL-2 treatment in patients results in activation of the immune system and creates the most suitable biological background for MLT. The finding that MLT stimulates IL-12 production from human monocytes only if incubated in presence of IL-2 further supports this concept. On the other hand, high concentrations of MLT have been found in human breast cancer tissue. The MLT concentration, which was 3 orders of magnitude higher than that present in the plasma, correlated positively with good prognostic markers such as estrogen receptor status and nuclear grade. Whether this relates to the immunoneuroendocrine action of MLT remains to be established. Clinical studies are needed on the effect of MLT in combination with IL-2 or other cytokines in cancer patients and viral diseases including HIV-infected patients.