The role of cognitive and social leisure activities in dementia risk: assessing longitudinal associations of modifiable and non-modifiable risk factors.

AIMS: With the projected surge in global dementia cases and no curative treatment available, research is increasingly focusing on lifestyle factors as preventive measures. Social and cognitive leisure activities are promising targets, but it is unclear which types of activities are more beneficial. This study investigated the individual and joint contribution of cognitive and social leisure activities to dementia risk and whether they modify the risks associated with other potentially modifiable and non-modifiable risk factors. METHODS: We used data from the English Longitudinal Study of Ageing (ELSA) from 7917 participants, followed up from 2008/2009 (Wave 4) until 2018/2019 (Wave 9) for incident dementia. Self-reported baseline cognitive activities (e.g. 'reading the newspaper'), the number of social memberships (e.g. being a member of a social club) and social participation (e.g. 'going to the cinema') were clustered into high and low based on a median split. Subsequently, their individual and joint contribution to dementia risk, as well as their interaction with other dementia risk factors, were assessed with Cox regression models, adjusting for age, sex, level of education, wealth and a composite score of 11 lifestyle-related dementia risk factors. RESULTS: After a median follow-up period of 9.8 years, the dementia incidence rate was 54.5 cases per 10.000 person-years (95% CI 49.0-60.8). Adjusting for demographic and other lifestyle-related risk factors, higher engagement in cognitive activities (HR = 0.58; 95% CI 0.40-0.84), a greater number of social memberships (HR = 0.65; 95% CI 0.51-0.84) and more social participation (HR = 0.71; 95% CI 0.54-0.95) were associated with lower dementia risk. In a joint model, only engagement in cognitive activities (HR = 0.60; 95% CI 0.40-0.91) and social memberships (HR = 0.75; 95% CI 0.56-0.99) independently explained dementia risk. We did not find any interaction with other modifiable and non-modifiable risk factors. CONCLUSIONS: Engagement in cognitive and social leisure activities may be beneficial for overall dementia risk, independent of each other and other risk factors. Both types of activities may be potential targets for dementia prevention measures and health advice initiatives.

Wound healing in MIP-1alpha(-/-) and MCP-1(-/-) mice.

A salient feature of normal wound healing is the development and resolution of an acute inflammatory response. Although much is known about the function of inflammatory cells within wounds, little is known about the chemotactic and activation signals that influence this response. As the CC chemokines macrophage inflammatory protein-1alpha (MIP-1alpha) and monocyte chemotactic protein-1 (MCP-1) are abundant in acute wounds, wound repair was examined in MIP-1alpha(-/-) and MCP-1(-/-) mice. Surprisingly, wound re-epithelialization, angiogenesis, and collagen synthesis in MIP-1alpha(-/-) mice was nearly identical to wild-type controls. In contrast, MCP-1(-/-) mice displayed significantly delayed wound re-epithelialization, with the greatest delay at day 3 after injury (28 +/- 5% versus 79 +/- 14% re-epithelialization, P < 0.005). Wound angiogenesis was also delayed in MCP-1(-/-) mice, with a 48% reduction in capillary density at day 5 after injury. Collagen synthesis was impeded as well, with the wounds of MCP-1(-/-) mice containing significantly less hydroxyproline than those of control mice (25 +/- 3 versus 50 +/- 8 microg/wound at day 5, P < 0.0001). No change in the number of wound macrophages was observed in MCP-1(-/-) mice, suggesting that monocyte recruitment into wounds is independent of this chemokine. The data suggest that MCP-1 plays a critical role in healing wounds, most likely by influencing the effector state of macrophages and other cell types.

Testosterone receptor blockade restores cellular immunity in male mice after burn injury.

Males are known to have increased risk for septic complications after traumatic injury, which appears to be mediated by the inhibitory effects of testosterone on immune function. The role of testosterone in immunity after burn injury, however, remains unclear. Herein, we examined the effects of a testosterone receptor antagonist, flutamide, on delayed type hypersensitivity response (DTH), splenocyte proliferation, interleukin (IL)-2 secretion, and IL-2 receptor (IL-2R) expression in male BALB/c mice subjected to a 15% total body surface area burn or sham injury. Burn- or sham-injured mice were given flutamide s.c. at 30 min and 24 h after injury. At 48 h, burn injury caused a 48% (P<0.001) decrease in DTH response; however, mice that received flutamide treatment did not demonstrate significant suppression of DTH. Likewise, splenocyte proliferation and IL-2 production were depressed in burned animals in comparison with sham-injured controls, and flutamide treatment resulted in a partial restoration of these responses. In vitro studies indicated that splenocytes from sham- and burn-injured mice were equally sensitive to the suppressive effects of 5alpha-dihydrotestosterone in regard to proliferation and IL-2 production. Further evaluation revealed a decrease in IL-2R expression on splenocytes from burned mice and a partial restoration of this expression with flutamide treatment. Thus blocking testosterone receptor activation improves the cellular immunity in thermally injured mice, possibly through restoration of IL-2 production and IL-2R expression. It remains to be determined whether the effects of testosterone in this injury model are direct or indirect.

Evidence of oxidative injury during aging of the liver in a mouse model.

The aim of the present study was to determine whether oxidative stress contributes to aging of the liver in a mouse model. Liver was obtained from young (3-5 months old) and aged (18-24 months old) mice. No age-induced gross changes in liver morphology were detected by light microscopy. Apoptosis was measured using the fragment end labeling of DNA for the immunohistochemical identification of the apoptotic nuclei. The total apoptotic cells represented 1% of the total cells in livers of young mice and 8% in those of aged mice. Among the total apoptotic cells in livers of aged animals, 15% were hepatocytes, 40% sinusoidal endothelial cells, and 45% bile duct cells. Hepatic lipid peroxidation, expressed as malonaldehyde levels, protein oxidation, measured by protein carbonyl content, and DNA oxidation, measured as 8-hydroxy-2'-deoxyguanosine (oxo(8)dG), were significantly increased in the livers of aged animals as compared to younger mice. The apoptotic cells presented elevated levels of oxidized DNA, detected by immunohistochemistry using an antibody directed against oxo(8)dG in serial sections. These results suggest that livers of aged animals presents evidence of increased oxidative injury and apoptosis. Because the apoptotic cells in the aged livers are mostly bile duct cells and sinusoidal endothelial cells, the cells most sensitive to oxidative stress injury, it can be hypothesized that reactive oxygen species-induced apoptosis in these cells contributes to the aging of the liver.

Differential production of prostaglandin E(2) in male and female mice subjected to thermal injury contributes to the gender difference in immune function: possible role for 15-hydroxyprostaglandin dehydrogenase.

We have previously reported a macrophage-mediated gender difference in postburn immunosuppression, which was dependent upon elevated levels of circulating 17beta-estradiol (E(2)) and, in part, interleukin-6. Herein we examined the role of prostaglandin E(2) (PGE(2)), a potent suppressor of cell-mediated immunity. Circulating levels of PGE(2) were significantly elevated in females but not males at 10 days postburn (P < 0.01), and indomethacin treatment fully restored the delayed-type hypersensitivity and splenocyte proliferative responses of thermally injured females. While there was no difference in cyclooxygenase-2 protein expression in the lungs and liver of thermally injured male and female mice, there was a marked decrease in the protein expression of 15-hydroxyprostaglandin dehydrogenase in females. These data demonstrate that PGE(2) is a critical mediator of immunosuppression in thermally injured female mice and that the increase in circulating PGE(2) is derived, in part, from decreased degradation and clearance of PGE(2).

Cellular immunity after ethanol exposure and burn injury: dose and time dependence.

Acute ethanol exposure prior to burn injury increases the immune dysfunction seen with burn alone, which has been partially attributed to increased circulating and splenic macrophage production of interleukin-6 (IL-6). The current studies examined the effect dose and timing of ethanol exposure prior to burn on cellular immunity. Mice with high (300 mg/dl) circulating levels of ethanol at the time of burn demonstrated further suppression of the delayed type hypersensitivity (DTH) and splenocyte proliferative responses in comparison to mice with moderate (100 mg/dl) ethanol levels. Interestingly, the increase in macrophage IL-6 secretion seen at the moderate dose was not augmented at the high dose; however, the circulating IL-6 levels did reveal a further increase at the high ethanol dose. There were no alterations in splenocyte subset populations and/or apoptosis at the moderate vs. the high ethanol dose. Moderate ethanol exposure 24 h, in comparison to 30 min, before injury resulted in similar decreases in the DTH. These results suggest that the dose-dependent effects of ethanol on immunity following burn injury are not the result of splenic macrophage IL-6 production as shown at the moderate dose and that the immune suppressive effects of ethanol in this model persist after it is cleared from the circulation.

Ethanol exacerbates T cell dysfunction after thermal injury.

To understand the mechanism of suppressed immunity following alcohol consumption and thermal injury, we analyzed T cell functions in a mouse model of acute alcohol exposure and burn injury. Mice with blood alcohol levels at approximately 100 mg/dl were given a 15% scald or sham injury. Mice were sacrificed 48 h after injury. Our data demonstrated a 20-25% decrease in Con A-mediated splenic T cell proliferation (p<0.01) and 45-50% decrease in interleukin-2 (IL-2) production (p<0.01) following burn injury compared to the T cells from sham animals. A further decrease in the proliferation (25-30%) and IL-2 production (40-45%) was detected in T cells derived from burned animals receiving alcohol as compared to burn alone. No significant change in the proliferation and IL-2 production was observed in splenic T cells derived from sham-injured mice regardless of alcohol exposure. Additionally, there was no demonstrable difference in splenocyte apoptosis in any treatment group. These results suggest that alcohol consumption prior to burn injury causes a greater decrease in T cell proliferation and IL-2 production compared to either burn or alcohol injury alone that may further attenuate the cell-mediated immunity and thus enhance susceptibility to infection.

The role of interleukin 6 in interferon-gamma production in thermally injured mice.

Following traumatic injury, patients suffer from compromised immunity increasing their susceptibility to infection. Previous studies from this laboratory demonstrated that female BALB/c mice subjected to a 15% total body surface area (TBSA) scald injury exhibit a decrease in cell-mediated immunity 10 days post-burn. Studies described herein revealed that concanavalin A (Con A; 2 microg/ml)-stimulated splenocytes from sham treated animals produced 3557+/-853 pg/ml of IFN-gamma while splenocytes from burn injured animals released two-fold more cytokine (P<0.05). To determine whether leukocyte production of IFN-gamma was under the influence of macrophages, splenic macrophage supernatants generated from burned animals were incubated with splenic lymphocytes from sham and burn animals. The amount of IFN-gamma released by lymphocytes from sham animals increased when cultured with macrophages from burned mice (P<0.05). This suggests that the increase in IFN-gamma production by unfractionated splenocytes in burned mice relative to sham treated animals is macrophage-dependent. Macrophage supernatants from burned mice released twice as much IL-6 as supernatants from sham animals (P<0.05), and when IL-6 was blocked in vivo, the amount of IFN-gamma production in burned mice decreased to sham levels (P<0.05). Thus, IL-6 mediates IFN-gamma production following burn.

Anti-interleukin-6 antibody treatment restores cell-mediated immune function in mice with acute ethanol exposure before burn trauma.

BACKGROUND: Previous studies from this laboratory reported that suppression of cell-mediated immune function was coincident with elevated interleukin (IL)-6 production after acute ethanol exposure before burn trauma, compared with either insult alone. The goal of this study was to investigate whether treatment with an anti-IL-6 antibody could restore immunocompetence in mice subjected to burn trauma with previous exposure to alcohol, as assessed by delayed-type hypersensitivity (DTH) and mitogen-induced splenocyte proliferative responses. METHODS: Mice given an ethanol treatment designed to reach a blood alcohol level of 100 mg/dl before a 15% total body surface area burn injury were treated with an anti-IL-6 antibody at 30 min and 24 hr postinjury. RESULTS: Burn/ethanol mice exhibited a 91% suppression of the DTH response ( < 0.01) and a 76% suppression of mitogen-induced splenocyte proliferation (p < 0.01) at 48 hr postinjury, along with increased levels of circulating and splenic macrophage-derived IL-6, compared with all other treatment groups. After anti-IL-6 antibody administration to burn/ethanol mice, there was a 25% (p < 0.05) and 63% (p < 0.01) recovery of the DTH and splenocyte proliferative responses, respectively. Addition of exogenous IL-6 to splenocyte cultures isolated from anti-IL-6 antibody-treated burn/ethanol mice resulted in a 70% inhibition of mitogen-induced proliferative responses (p < 0.03). CONCLUSIONS: These data confirm previous findings that burn in combination with acute ethanol exposure suppresses cell-mediated immune function compared with either insult alone. Furthermore, the ability of the anti-IL-6 antibody treatment to improve cellular immune responses in the burn/ethanol group suggests that blocking this cytokine may be beneficial for the ethanol-exposed, thermally injured individual.

Dose-dependent effect of ethanol on hepatic oxidative stress and interleukin-6 production after burn injury in the mouse.

BACKGROUND: Burned patients with detectable blood alcohol levels (BAL) show an elevated mortality rate. Interleukin (IL)-6 and reactive oxygen species (ROS) production is stimulated independently by alcohol and burn injury. The aim of the study was to determine whether increasing levels of alcohol differentially enhance the hepatic production of IL-6 and ROS after burn in a murine model of dorsal scald injury. Groups of mice received either saline or alcohol intraperitoneally to reach a BAL of 100 mg/dl or 300 mg/dl at the time of burn (15% total body surface scald) or sham injury. RESULTS: Burn injury alone resulted in a low mortality rate at 24 hr after injury as did the burn group with a BAL of 100 mg/dl (15%), whereas 57% of the mice burned with a BAL of 300 mg/dl did not survive (p = 0.02). Twenty-four hours after burn or sham injury, IL-6 levels were measured by enzyme-linked immunosorbent assay in serum and liver. In the saline-treated group, IL-6 circulating and hepatic levels rose after burn injury (p < 0.03). Circulating IL-6 levels in sham mice increased 1.5-fold in the group with a BAL of 100 mg/dl and 3-fold in those with a BAL of 300 mg/ml (p = 0.005 versus burn-injured, saline-treated). IL-6 hepatic production after burn injury was higher in the mice with a BAL of 300 mg/dl than in those with a BAL of 100 mg/dl and the saline-treated group (p = 0.001). Among the burned mice, alcohol exposure increased hepatic ROS production, measured by lipid peroxidation and protein oxidation, in a dose-dependent manner. CONCLUSIONS: Alcohol enhances in a dose-dependent manner the hepatic production of IL-6 induced by burn injury through the modulation of oxidative stress. The increased mortality rate of mice exposed to alcohol and burn injury may be due to the adverse effect on immune function induced by IL-6 elevation.

Gender difference in cell-mediated immunity after thermal injury is mediated, in part, by elevated levels of interleukin-6.

The gender difference in normal immune function has been well documented, however, there is only limited information regarding whether such a difference occurs after injury. To investigate this, we examined cell-mediated immune responses in male and female mice given a 15% total body surface area dorsal scald or sham injury. Both delayed-type hypersensitivity (DTH) and splenocyte proliferative responses were significantly suppressed in males at 1 day and in females at 7 and 10 days post burn (P < 0.01). The decreased splenocyte proliferation was found to be macrophage-dependent and suppression of both immune parameters corresponded with elevated interleukin-6 (IL-6) levels. Furthermore, post-burn treatment with an anti-IL-6 antibody partially restored the DTH response in males at 1 day and females at 10 days post injury and completely restored splenocyte proliferation. These data demonstrate a possible mechanism for the gender difference in cell-mediated immune responses after thermal injury.

Estrogen mediates the sex difference in post-burn immunosuppression.

Previous studies in our laboratory have demonstrated that cell-mediated immune function was suppressed in female, but not male, mice at 10 days after burn injury and was mediated, in part, by increased production of interleukin-6 (IL-6). Because 17beta-estradiol (E(2)) influences immune function after trauma and the hormone is known to regulate IL-6 production, the effect of E(2) on immune function after thermal injury was examined. Increased circulating concentrations of E(2) corresponded with suppressed delayed-type hypersensitivity (DTH) and splenocyte-proliferative responses, and increased circulating concentrations of IL-6 in female mice after burn. Ovariectomy restored the suppressed DTH response and decreased IL-6 concentrations, and administration of exogenous E(2) to both ovariectomized females and intact male mice resulted in a suppressed DTH response. In addition, in vitro treatment with E(2) suppressed splenocyte proliferation in a macrophage-dependent manner and enhanced macrophage production of IL-6. These results strongly suggest that the sex difference in cell-mediated immunity 10 days after burn injury is mediated by altered concentrations of E(2), which in turn modulate key macrophage-derived immunoregulatory cytokines.

Neutrophil chemokine production in the skin following scald injury.

The present study was conducted to determine whether local production of neutrophil chemoattractant cytokines preceded the influx of neutrophils following dermal scald injury. To accomplish this, dermal tissue was examined for inflammatory infiltrate and the level of KC, a murine homolog of human interleukin-8, at various time points after scald injury. The studies reveal that there was a largely neutrophilic infiltrate at 1 day post-injury which persisted for 4 days. Dermal KC levels increased significantly at 4 h, returned to baseline at 8 h and were elevated again from 1 to 3 days post-burn (P < 0.01). At 3 days post-burn, KC was elevated 15-fold above the level in sham treated mice (P < 0.01). These observations demonstrate that the influx of neutrophils into the skin follows the expression of KC in the skin. This suggests that it should be possible to alter neutrophil accumulation at the wound site by manipulating the local chemokine signal.

Elevation in pulmonary neutrophils and prolonged production of pulmonary macrophage inflammatory protein-2 after burn injury with prior alcohol exposure.

Various studies have shown that alcohol exposure before thermal injury leads to increased morbidity and mortality. Pulmonary failure is a major complication seen in these patients. This study examines the effects of prior alcohol exposure on lung pathology after burn injury. There is a marked increase in neutrophil recruitment in the lung after thermal injury, and herein we show that this appears to be significantly elevated in animals given alcohol before burn injury. Consequently, we chose to determine whether there is a difference in pulmonary production of macrophage inflammatory protein (MIP)-2, a potent neutrophil chemoattractant, in mice subjected to a 15% total body surface area scald (or sham) injury with or without prior ethanol treatment. Lung tissue was obtained at various time points after injury and homogenates were assayed for MIP-2 by enzyme-linked immunosorbent assay. At 2 h after injury, peak levels of the chemokine were produced in both burn and burn + alcohol-treated mice. This represents a 7-fold increase above baseline. In mice exposed to burn injury alone, the level of MIP-2 returned to baseline within 8 h. In contrast, mice given alcohol before burn injury continued to show elevated levels of the chemokine at 8 h, after which MIP-2 decreased. This study may provide a basis for understanding the mechanism responsible for the increased neutrophil presence in the lung after thermal injury in individuals who have consumed alcohol. Subsequently, this may lead to the enhanced neutrophil-mediated pulmonary damage observed in these patients.

Bilateral fascia lata patch grafts in a patient with progressive scleromalacia perforans.

This study was performed to evaluate the use of autogenous fascia lata patch grafts with systemic immunosuppression in the treatment of progressive bilateral scleromalacia perforans. Autogenous fascia lata was compared with donor bank sclera and was demonstrated to be more suitable for this condition.

The effect of postnatal growth retardation on abnormal neovascularization in the oxygen exposed neonatal rat.

Severe retinopathy of prematurity (ROP) occurs in the smallest and sickest of premature infants. We hypothesized that, in a rat model of oxygen induced retinopathy, abnormal neovascularization would occur more frequently in larger litters where the pups are subject to postnatal growth retardation. Four litters of newborn Sprague-Dawley rats were studied; rats were randomly mixed to form two large litters (n = 25 each) and two small litters (n = 10 each). All litters were exposed to 7 days cyclic hyperoxia and hypoxia followed by 5 days in room air. ADPase stained retinae were evaluated in a masked manner for the presence and severity of abnormal neovascularization. Fluorescein perfused retinae were digitized and the ratios of vascularized:total retinal area were calculated using computer assisted image analysis. As expected, final weight in the large litters was less than in the small litters (15.3 +/- 3.8g vs. 23.4 +/- 2.1g, p < 0.001). Neovascularization occurred in 53% of rats in the large litters vs. 15% in the small litters (p = 0.009). Rats with retinae demonstrating neovascularization were smaller than those without (16.2 +/- 4.7g vs. 19.6 +/- 5.0g, p = 0.016). The severity of neovascularization in clock h was inversely correlated with final weight (rs = -0.35, p = 0.01) and ratio of vascularized:total retina area (rs = -0.46, p < 0.001). Smaller rat pups raised in larger litters, with resultant growth retardation, develop more frequent and more severe abnormal retinal neovascularization. Our results correlate with clinical experience in the premature infant.

The effect of litter size on normal retinal vascular development in the neonatal rat.

Many animal models of retinal disease use the neonatal rat. Raising rat pups in large litters has been shown to result in postnatal growth retardation. We investigated the effect of litter size on the normal postnatal vascularization of the neonatal rat retina. Sixty-six newborn rat pups were divided among 5 nursing mothers into 3 small litters (n = 10) and 2 large litters (n = 18). On day 6 of life the rats were sacrificed and total retinal and vascularized retinal areas analyzed. The total retinal area was reduced in the rats raised in larger litters (28.6 mm2 vs. 25.9 mm2 p < 0.001) but there was a more pronounced reduction in vascularized retinal area (67% vascularized vs. 54% vascularized, p < 0.001). Postnatal vascularization of the normal rat retina may be influenced by litter size.

The effect of raised inspired carbon dioxide on developing rat retinal vasculature exposed to elevated oxygen.

Hyperoxia is a risk factor for retinopathy of prematurity (ROP), a blinding disease in infants. However, ROP develops in human infants without raised arterial oxygen levels, such as in cyanotic congenital heart disease. In these infants raised pCO2 may be a risk factor. We investigated the effect of inspired CO2 on oxygen induced retinopathy in the rat. 56 newborn Sprague-Dawley rats were exposed to high cyclical O2 for seven days. In a control group, 27 rats were exposed to negligible CO2 by the use of soda lime. In the high CO2 group, 29 rats were exposed to elevated CO2 by omitting soda lime from their chambers. Rats in both groups had a recovery period of three days in room air following cyclical O2 exposure. On the eleventh day all rats were sacrificed after intracardiac injections of fluorescein under deep anesthesia and the retinae were dissected and flat mounted for fluorescent microscopy. The ratio of vascularized:total retinal area was calculated using computer assisted image analysis. In the high CO2 group 62% +/- 7% SD of the retina was vascularized vs. 81% +/- 7% in low CO2 group (p < 0.001). Elevated inspired CO2 results in pronounced retardation of retinal vascular development in neonatal rats exposed to fluctuating raised oxygen.