The impact of air pollution on hospital admission for respiratory and cardiovascular diseases in an oil-rich country.

OBJECTIVES: Aim of this study was to evaluate the impact of air pollution on hospital admissions for respiratory and cardiovascular diseases in an oil rich developing country, State of Qatar. METHODS: A prospective cohort population based study was conducted at different stations of Qatar during the period (2002-2005) for recording the concentration of air pollutants daily for sulphur dioxide (SO2), nitric oxide (NO), nitrogen dioxide (NO2), carbon monoxide (CO), ozone (O3) and particulate matter (PM10). Hospital admission data were collected from the inpatient discharge database of the Medical Records Department, Hamad General Hospital. RESULTS: An average of 5.36 admissions from ischemic heart diseases was counted daily in all the population which was even higher than the respiratory diseases (3.4/day). Minimum temperature was inversely correlated with all pollutants except for O3 and SO2. CONCLUSION: There was an association between increasing air pollutant levels and patients admitted for respiratory and cardiovascular diseases.

The impact of air pollution on hospital admission for respiratory and cardiovascular diseases in an oil and gas-rich country.

OBJECTIVES: Aim of this study was to evaluate the impact of air pollution on hospital admissions for respiratory and cardiovascular diseases in an oil rich developing country, State of Qatar. METHODS: A prospective cohort population based study was conducted at different stations of Qatar during the period (2002-2005) for recording the concentration of air pollutants daily for sulphur dioxide (SO2), nitric oxide (NO), nitrogen dioxide (NO2), carbon monoxide (CO), ozone (O3) and particulate matter (PM10). Hospital admission data were collected from the inpatient discharge database of the Medical Records Department, Hamad General Hospital. RESULTS: An average of 5.36 admissions from ischemic heart diseases was counted daily in all the population which was even higher than the respiratory diseases (3.4/day). Minimum temperature was inversely correlated with all pollutants except for O3 and SO2. CONCLUSION: There was an association between increasing air pollutant levels and patients admitted for respiratory and cardiovascular diseases.

Habituation and cross-sensitization of stress-induced hypothalamic-pituitary-adrenal activity: effect of lesions in the paraventricular nucleus of the thalamus or bed nuclei of the stria terminalis.

Habituation of the hypothalamic-pituitary-adrenal (HPA) response to chronic intermittent restraint stress (30 min/day for 15 days) and the cross-sensitization to a heterotypic stress [i.p. lipopolysaccharide (LPS)] were investigated in intact male Sprague Dawley rats, and in rats bearing quinolinic acid lesions to the medial anterior bed nuclei of the stria terminalis (BST) or anterior region of the paraventricular nucleus of the thalamus (PVT). In intact animals, a single period of restraint increased plasma corticosterone levels at 30 min and led to an increase in corticotropin-releasing hormone (CRH) mRNA levels in the PVN at 3 h. LPS had a smaller effect on corticosterone and more variable effect on CRH mRNA. Chronic intermittent restraint stress caused a decrease in body weight and increase in adrenal weights, with concomitant increase in basal corticosterone levels. These animals also displayed marked habituation of the corticosterone and CRH mRNA responses to the homotypic stress of restraint, but no loss of the corticosterone response to the heterotypic stress of LPS and a cross-sensitization of the CRH mRNA response. This pattern of stress responses in control and chronically stressed animals was not significantly affected by lesions to the PVT or BST, two areas which have been implicated in the coping response to stress. Thus, these data provide evidence for independent adaptive mechanisms regulating HPA responses to psychological and immune stressors, but suggest that neither the medial anterior BST nor the anterior PVT participate in the mechanisms of habituation or cross-sensitization.

Hypothalamic-pituitary-adrenal function.

Basal hypothalamic-pituitary-adrenal (HPA) function is characterised by pulses of corticosterone secretion followed by a transient refractory period when the axis appears to be inhibited. In females pulses of corticosterone secretion occur approximately once per hour with variation in pulse amplitude underlying a diurnal rhythm. Males show smaller pulses of secretion which become widely spaced during the early light phase nadir. Pulsatility is altered by genetic programming, early life experiences and reproductive status. Activation of the HPA axis during adjuvant induced arthritis results in an increase in the pulse frequency. This is associated with a marked change in hypothalamic gene expression with a diminution of CRH mRNA and a marked increase of AVP mRNA which becomes the predominant HPA secretagogue.

Peripartum plasticity within the hypothalamo-pituitary-adrenal axis.

The hypothalamo-pituitary-adrenal (HPA) axis plays important roles in the adaptive changes in physiology that occur during pregnancy and lactation. Although the axis still exhibits a pulsatile pattern of secretion, the normal diurnal rhythm of pulse amplitude is lost during lactation, such that mean basal levels remain constant throughout the day. In addition, the peripartum period is associated with a remarkable plasticity in stress-induced HPA activity, in that the increase of HPA activity normally seen in response to either physical or psychological stresses in the non-reproductive state become severely attenuated or absent in the lactating animal. This stabilization of both basal and stress-induced HPA activity may be important for maintaining a constant endocrine environment, thereby preventing any programming effects on the developing offspring. Attenuation of the stress response is initiated in late pregnancy and is temporally associated with luteolysis, indicating possible steroid hormone involvement. Indeed, mimicking the luteolytic changes in oestrogen and progesterone levels in non-pregnant animals induces a similar attenuation of the stress response. Furthermore down-regulation of the stress response is, at least in part, centrally mediated since in the period following luteolysis rats will show a decreased level of stress-induced neuronal activation of the PVN, as measured by the expression of either c-fos or CRH mRNAs. Persistence of this adapted state is dependent upon the continued suckling stimulus, as removal of the offspring litter rapidly leads to resumption of HPA responses to and the appearance of an exaggerated diurnal rhythm. The underlying mechanisms responsible for this stress hyporesponsiveness may include plasticity of noradrenergic and oxytocin pathways. In view of its role in other reproductive behaviors, a stress-inhibiting effect of oxytocin may reflect a more widespread co-ordinating role in the peripartum animal.

Are adhesion molecules involved in stress-induced changes in lymphocyte distribution?

Acute psychological stress is associated with important changes in circulating cell populations and reductions in cell-mediated immune responses. However, the mechanisms underlying these phenomena are poorly understood. In this study, we investigated (i) acute and chronic restraint stress effects in Sprague-Dawley rats on peripheral lymphocyte subsets and (ii) adhesion molecule (beta2 integrins) expression and (iii) also determined whether glucocorticoids could underlie stress-related changes in cellular redistribution. We observed time-dependent changes in lymphocyte distribution including decreased (-21%) percentages of peripheral T helper cells and increased (88%) NK cell numbers following acute brief restraint. Acute stress was also found to overall upregulate beta2-integrin (CD11a and CD11b) expression on T cells and to raise (1049%) plasma corticosterone levels. However, this stress response was found habituated (-75% vs. acute) in the animals previously exposed to chronic restraint stress. Stress effects on circulating lymphocytes were not observed in animals previously exposed to chronic intermittent restraint stress or chronically stressed animals re-exposed to the same stressor. Our results indicate that 1) stress alters lymphocyte distribution, 2) that adhesion molecules may be involved in stress-induced alterations of T-cell distribution and 3) that these changes may be related to circulating glucocorticoids and subjected to adaptation with repeated stress exposure.

Restraint stress is associated with changes in glucocorticoid immunoregulation.

Psychological stress has been associated with activation of the hypothalamic-pituitary-adrenal (HPA) axis and impaired cell-mediated immune (CMI) responses. There is also evidence suggesting that intermittent chronic stress differentially alters CMI across different immune compartments, but the mechanisms underlying this phenomenon have not been explored in detail. In the present study, we investigated (i) acute and chronic restraint stress effects in Sprague-Dawley rats on both peripheral blood lymphocyte (PBL) and splenocyte mitogen-induced proliferation and (ii) also determined whether differential stress effects within these immune compartments might reflect alterations in lymphocyte sensitivity to glucocorticoids. It was found that while acute stress exposure significantly raised plasma corticosterone levels (1048% vs. controls, P<.001), this response was attenuated in the animals previously exposed to chronic intermittent stress (-79.66% vs. acute; P<.001). Acute stress increased phytohemagglutinin (PHA)-induced lymphocyte proliferation in the spleen (69.04%, P=.01) and suppressed PBL proliferation (-45.52%, P<.001). Neither of these changes were observed following chronic stress. We also demonstrated that reexposure to the stressor rapidly increased splenocyte sensitivity to in vitro dexamethasone (P<.05) and corticosterone (P<.05) in chronically stressed rats. Our data (1) confirm that acute stress is associated with compartment-specific changes in CMI function, (2) indicate that chronic stress is associated with habituated endocrine and immune responses and (3) that stressor exposure rapidly alters splenocyte sensitivity to glucocorticoids and we suggest that the latter may contribute to differential stress effects across immune compartments.

Environmental factors and heatstroke.

The objective of this study was to determine the extent of the influence of temperature and humidity on the number of heatstroke presentations. Three hundred and forty-five labourers presented to the Accident and Emergency Hospital in Abu Dhabi with heatstroke during a 3 month summer period. There was no significant predictive association between the maximum daily temperature and/or humidity and the presentation of heatstroke. There was no significant association with the maximum temperature on the previous day, day of the week or temperature trend. The largest statistical correlation was between the maximum temperature and humidity and the log of the number of cases. It is possible that there are other significant explanatory variables that we have not included in the model.

Correlates and Predictors of Self-reported Psychological and Physical Morbidity in Chronic Caregiver Stress.

An investigation was conducted to explore: (1) whether psychological and physical morbidity share similar psychosocial determinants; (2) the long-term stability of these determinants; and (3) the role of neuroticism in predicting psychological and physical morbidity. Fifty spousal caregivers of dementia patients were recruited into a 12-month study. Participants were followed up at six-monthly interva ls during which they completed scales measuring psychosocial mediators, psychological morbidity, physical morbidity and neuroticism. Psychological morbidity was influenced primarily by indices of coping and neuroticism. Physical morbidity was influenced primarily by indices of psychological morbidity (increased psychological morbidity was associated with perceptions of greater physical morbidity). Neuroticism exhibited significant cross-sectional and longitudinal relationships with the indices of psychological morbidity, but only cross-sectional relationships with the indices of physical morbidity.

The role of stressors and psychosocial variables in the stress process: a study of chronic caregiver stress.

OBJECTIVE: An investigation was conducted 1) to examine the relative importance of stressor types (ie, daily hassles, caregiving-specific stressors, and life events) on the stress response, 2) to assess the stability of relationships between psychosocial variables and stress over a 6-month period, and 3) to explore how the nature and magnitude of the contributions made by stressors and psychosocial factors to the stress process varied according to the qualitative characteristics of the stress response (ie, anxiety, depression, and stress). METHODS: Fifty spousal caregivers of patients with dementia were recruited and asked to participate in a detailed psychosocial evaluation at 3-month intervals; the evaluation involved measurement of stressor frequency, psychosocial variables, and indices of the stress response (ie, anxiety, depression, and stress). RESULTS: The data revealed that the effects of stressors and psychosocial factors on the stress response were considerable (accounting for 49-63% of the variance in stress response measures). Furthermore, there was some evidence of stability in the effects of the stressor and mediator variables on the stress response. Specifically, the contributions of life events and caregiver difficulties were largely consistent at both 3 and 6 months, and the psychosocial factor of "reactive coping and self-appraisal" influenced all three stress response indices at both 3 and 6 months. CONCLUSIONS: There is some evidence of stability in the effects of stressors and psychosocial variables on the stress process over a 6-month period. However, it would also seem that the nature of the stress process differs according to the qualitative characteristics of the stress response.

Early-life exposure to endotoxin alters hypothalamic-pituitary-adrenal function and predisposition to inflammation.

We have investigated whether exposure to Gram-negative bacterial endotoxin in early neonatal life can alter neuroendocrine and immune regulation in adult animals. Exposure of neonatal rats to a low dose of endotoxin resulted in long-term changes in hypothalamic-pituitary-adrenal (HPA) axis activity, with elevated mean plasma corticosterone concentrations that resulted from increased corticosterone pulse frequency and pulse amplitude. In addition to this marked effect on the development of the HPA axis, neonatal endotoxin exposure had long-lasting effects on immune regulation, including increased sensitivity of lymphocytes to stress-induced suppression of proliferation and a remarkable protection from adjuvant-induced arthritis. These findings demonstrate a potent and long-term effect of neonatal exposure to inflammatory stimuli that can program major changes in the development of both neuroendocrine and immunological regulatory mechanisms.

Significance of pulsatility in the HPA axis.

A stress-free automated blood sampling system has been employed to demonstrate pulsatile hypothalamo-pituitary-adrenal (HPA) activity in the rat. In females, pulses of corticosterone secretion occur approximately once/hour throughout the 24 h cycle, with variation in pulse amplitude underlying a diurnal rhythm. Males show smaller pulses of secretion which become widely spaced during the early light phase nadir. Ageing does not affect the occurrence of pulses but the diurnal variation is lost. Analysis of the relationship between the HPA response to an acute noise stress and its coincidence with the various phases of the pulse, suggests that pulsatile activity arises from alternating periods of activation and suppression. Responses to i.v. corticotropin-releasing factor are not affected by pulse phase, indicating that this relationship is not generated at the pituitary-adrenal level. This phase relationship holds for all strains of rat except the hyperresponsive Fischer-344 in which an exaggerated stress response arises from a lack of phase-dependent suppression. Patterns of pulsatile activity are also modulated by neonatal programming or chronic HPA activation arising from adjuvant-induced arthritis, with consequent impact upon the response to acute stimuli. Thus, variations in the patterns of pulsatile activity are important determinants of both basal secretion and acute responses of the HPA axis.

Chronic stress in caregivers of dementia patients is associated with reduced lymphocyte sensitivity to glucocorticoids.

Caring for the chronically ill is associated with chronic distress. In view of the adverse effects of distress on cellular immune function, such distress may have implications for health. Indeed, it has been proposed that the hypothalamic-pituitary-adrenal (HPA) axis is a potential psychobiological mediator of these effects. In this study, we observed that elderly caregivers experienced greater distress and increased salivary cortisol than non-caregivers. In addition, caregivers had blunted mitogen-induced lymphocyte proliferation, lower mitogen-induced IL-2 production, and reduced lymphocyte sensitivity to glucocorticoids. These results indicate that chronic distress is associated with impaired cell-mediated immunity which is, in turn, associated with elevated basal steroid levels and altered steroid immunoregulation at the level of the lymphocyte.

Manometry based randomised trial of endoscopic sphincterotomy for sphincter of Oddi dysfunction.

BACKGROUND: Endoscopic sphincterotomy for biliary-type pain after cholecystectomy remains controversial despite evidence of efficacy in some patients with a high sphincter of Oddi (SO) basal pressure (SO stenosis). AIM: To evaluate the effects of sphincterotomy in patients randomised on the basis of results from endoscopic biliary manometry. METHODS: Endoscopic biliary manometry was performed in 81 patients with biliary-type pain after cholecystectomy who had a dilated bile duct on retrograde cholangiography, transient increases in liver enzymes after episodes of pain, or positive responses to challenge with morphine/neostigmine. The manometric record was categorised as SO stenosis, SO dyskinesia, or normal, after which the patient was randomised in each category to sphincterotomy or to a sham procedure in a prospective double blind study. Symptoms were assessed at intervals of three months for 24 months by an independent observer, and the effects of sphincterotomy on sphincter function were monitored by repeat manometry after three and 24 months. RESULTS: In the SO stenosis group, symptoms improved in 11 of 13 patients treated by sphincterotomy and in five of 13 subjected to a sham procedure (p = 0.041). When manometric records were categorised as dyskinesia or normal, results from sphincterotomy and sham procedures did not differ. Complications were rare, but included mild pancreatitis in seven patients (14 episodes) and a collection in the right upper quadrant, presumably related to a minor perforation. At three months, the endoscopic incision was extended in 19 patients because of manometric evidence of incomplete division of the sphincter. CONCLUSION: In patients with presumed SO dysfunction, endoscopic sphincterotomy is helpful in those with manometric features of SO stenosis.

Alterations in hypothalamic-pituitary-adrenal function correlated with the onset of murine SLE in MRL +/+ and lpr/lpr mice.

Systemic lupus erythematosus (SLE) is a spontaneously occurring, chronic autoimmune disease that can manifest neuropsychiatric abnormalities. The pathways mediating these central changes are not known; however, neuroendocrine alterations associated with inflammation may play a role. Predisposition to and progression of autoimmune disease has been associated with altered hypothalamic-pituitary-adrenal (HPA) function and inflammation has been reported to alter hypothalamic regulation of HPA responses. We investigated whether disease progression in a murine model of systemic lupus erythematosus (MRL +/+. MRL lpr/lpr) resulted in altered expression of HPA regulatory peptides at the level of the hypothalamus and how these alterations related to circulating levels of corticosterone, corticosterone binding globulin, and autoantibody titers. We report that as MRL +/+ and MRL lpr/lpr mice age and circulating levels of autoantibodies increase, there is a decrease in hypothalamic CRH mRNA expression and finally an increase in AVP mRNA expression. We also report that associated with increased autoantibody levels, disease progression, and altered hypothalamic peptide expression there is an increase in circulating levels of corticosterone and a trend for levels of corticosterone binding globulin to decrease. Our data complement previous observations of altered peptidergic regulation of the HPA axis and increased HPA activity during chronic inflammation in exogenously induced rodent models of chronic inflammation and indicate that similar processes may occur in spontaneous murine models of SLE.

The hypothalamic-pituitary-adrenal axis response to endotoxin is attenuated during lactation.

Pregnancy and lactation are times of prolonged physiological changes affecting the neuroendocrine and immunological systems. One well-characterized change is the neuroendocrine hyporesponsiveness to acute stressful stimuli. We have now designed studies to see whether there is an alteration in the response of the hypothalamic-pituitary-adrenal (HPA) axis to an immunological inflammatory challenge and to ascertain whether lactating animals show altered neural and endocrine responses to inflammatory stimuli. Lactating (day 9-12 postpartum) or virgin control Sprague-Dawley female rats were injected with either 200 microg of endotoxin (lipopolysaccharide, LPS ) or sterile saline given i.p. Trunk blood or jugular blood was collected from the animals at 2 h or hourly over 6 h after injection. Both plasma adrenocorticotropic hormone (ACTH) and corticosterone concentrations were significantly higher in saline treated lactating animals compared with the virgin group. LPS significantly elevated circulating levels of plasma ACTH and corticosterone in both virgin and lactating animals compared with saline controls, however, hormone responses to LPS were significantly reduced in lactating animals relative to virgin controls. Corticosterone-binding globulin concentrations were lower in lactating animals compared to virgin animals and LPS decreased concentrations in virgin, but not lactating rats. Analysis of cfos mRNA in the paraventricular nucleus (PVN) of the hypothalamus revealed that 2 h following injection there was a increase in cfos expression only in the virgin animals treated with LPS, compared to all other treatment conditions. Corticotropin-releasing hormone (CRH) mRNA expression was overall greater in virgin animals, but was increased to similar extent in both virgin and lactating animals treated with LPS. Primary arginine vasopressin (AVP) mRNA transcripts were increased 2 h following LPS injection, but a greater increase in expression was seen in virgin animals. These data demonstrate that there is a lower level of free circulating glucocorticoid in response to inflammatory stimuli and suggests that communication between the immune and endocrine systems may be altered during lactation.

Chronic stress in elderly carers of dementia patients and antibody response to influenza vaccination.

BACKGROUND: There are many reports of psychological morbidity in spousal carers of patients with dementia. The consequences of this increased stress on the immune system are unclear. We investigated whether antibody responses to influenza vaccination differed between carers and a control group, and the relation of the antibody response to the hypothalamic-pituitary-adrenal (HPA) axis. METHODS: 50 spousal carers of dementia patients, median age 73 years (IQR 66-77), and 67 controls (68 years [66-71]) of similar socioeconomic status were enrolled. Anxiety and depression were measured by the Savage Aged Personality Screening Scale and stress by the Global Measure of Perceived Stress scale. Principal-component analysis was used to yield a summary score of emotional distress from these two scales. Salivary cortisol concentrations were measured over a single day at three times (0800-1000, 1100-1300, and 2000-2200). Participants received a trivalent influenza vaccine and IgG antibody titres to each strain were measured on days 0, 7, 14, and 28. FINDINGS: Mean scores of emotional distress were significantly higher in carers at each time point than in controls (all p<0.0003). Mean (SD) salivary cortisol concentrations, calculated as area under the curve (AUC), were higher in carers than controls at all three assessments (6 months 16.0 [8.0] vs 11.2 [4.4], p=0.0001; respectively). Eight (16%) of 50 carers and 26 (39%) of 67 controls had a four-fold increase in at least one of the IgG titres (p=0.007). There was an inverse relation between AUC cortisol and IgG antibody titre to the Nanchang strain that was significant on day 14 (r=-0.216, p=0.039). INTERPRETATION: Elderly carers of spouses with dementia have increased activation of the hypothalamic-pituitary-adrenal axis and a poor antibody response to influenza vaccine. Carers may be more vulnerable to infectious disease than the population of a similar age.

Differential immune reactivity to stress in BALB/cByJ and C57BL/6J mice: in vivo dependence on macrophages.

Inbred BALB/cByJ and C57BL/6J mice not only differ in their neuroendocrine and behavioral reactivity to stress, but also their ability to mount appropriate immune responses to various pathogens. Because evidence suggests that stress may bias humoral or cell-mediated immune responses in these mouse strains, we assessed the effects of acute (1 h) physical restraint on the humoral immune response to keyhole limpet hemocyanin (KLH). Restraint exposure in close proximity to immunization with KLH enhanced the number of primary antigen-specific IgM and IgG producing splenic B cells in BALB/cByJ mice, but not in C57BL/6J mice. These effects might be determined at the level of macrophage antigen presenting cells, because BALB/cByJ mice immunized with KLH as a particulate antigen (i.e., encapsulated in liposomes) displayed the same stressor enhanced antibody response as they did to free, unencapsulated KLH. In addition, these mice showed enhanced production of the IgG1 subtype of IgG, but not the IgG2a subtype. Conversely, stressed C57BL/6J mice revealed an enhanced IgG2a response, although this was observed only under conditions of immunization with liposome-encapsulated KLH. In a final experiment involving only the BALB/cByJ strain, the depletion of macrophages in the spleen by administration of liposomes containing dichloromethylene biphosphonate (DMDP) 2 days before immunizing the mice with free KLH and restraint exposure, blocked the restraint-induced enhancement of humoral immune responses. These data suggest a possible intermediary role for macrophages in stressor-induced immunomodulation in vivo, which may be a potential point of divergence that explains the differential immune reactivity to KLH of BALB/cByJ and C57BL/6J mice exposed to an acute stressor.

Inflammatory disease as chronic stress.

It is now established that communication between the CNS and the immune system is bidirectional, that endocrine factors can alter immune function and that immune responses can alter both endocrine and CNS responses. In many respects CNS and endocrine responses to acute inflammation are similar to the changes associated with acute stress exposure. In contrast, during chronic inflammation associated with adjuvant induced arthritis (AA), although circulating levels of corticosterone are increased, the peptidergic regulation of the hypothalamus is different from that seen during acute stress. As the disease progresses, a paradoxical reduction occurs in CRH mRNA in the paraventricular nucleus (PVN), whereas PVN AVP mRNA increases. These data suggest that there is increased expression of AVP mRNA within the CRH cells of the PVN with an increased emphasis on AVP regulation of HPA output. Additionally, HPA function is altered during chronic inflammation such that responses to psychological stress (i.e. restraint) are significantly dampened, while responses to further inflammatory challenges are maintained. These data suggest that alterations in PVN peptide colocalization may be important in regulating the progression of peripheral inflammatory responses and that the effects of inflammation on the hypothalamus alter stress-responsive systems. In addition to the AA model, we have similarly observed alterations in PVN peptide mRNA expression with disease onset in the murine MRL lpr/lpr and MRL +/+ model of SLE. Disease onset in murine SLE is spontaneous and does not rely on exogenous application of adjuvant; however, decreased levels of CRH in the PVN were observed from early disease onset in this animal model. It is suggested that alterations in CRH regulation in response to either acute or chronic inflammation may contribute as etiological factors to both psychiatric (i.e. neuropsychiatric SLE) and stress-related disease.