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The aim of this narrative review was to demonstrate how the notion of allostatic load (AL) relates directly to the mental health disparities observed between Indigenous and non-Indigenous Australians. We also endeavored to synthesize the results of the limited number of studies examining stress and AL in Indigenous Australians in order to explore the potential public health benefits of the AL concept. A range of literature examining health inequalities, psychosocial determinants of mental illness and AL was explored to demonstrate the applicability of stress biology to the significant mental health burden faced by Indigenous Australians. Furthermore, all original studies indexed in MEDLINE that provided quantitative data on primary stress biomarkers in Indigenous Australians were selected for review. Evidence of hypothalamic-pituitary-adrenal axis dysregulation and increased AL is apparent even in the handful of studies examining stress biomarkers in Indigenous Australians. Urinary, salivary, hair and fingernail cortisol, hair cortisone, urinary epinephrine, heart rate variability and the cortisol awakening response are all AL parameters which have been shown to be dysregulated in Indigenous Australian cohorts. Furthermore, associations between some of these biomarkers, self-perceived discrimination, exposure to stressful life events and symptoms of psychiatric disorders in Indigenous Australians have also been demonstrated. The continued assessment of AL biomarkers and their relationship with past traumas, lifetime stressors and socio-economic factors amongst Indigenous Australians is important to addressing the mental health this population. Measurement of AL biomarkers in a culturally appropriate manner may lead to more targeted preventative measures, interventions and policies, which mitigate the effects of stress at both the individual and societal level.

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Various studies have shown that increased activity of the hypothalamic-pituitary-adrenal (HPA) axis can predict the onset of adolescent depressive symptomatology. We have previously shown that adolescents making the transition to high school present a significant increase in cortisol levels, the main product of HPA axis activation. In the present study, we evaluated whether a school-based education program developed according to the current state of knowledge on stress in psychoneuroendocrinology decreases cortisol levels and/or depressive symptoms in adolescents making the transition to high school. Participants were 504 Year 7 high school students from two private schools in the Montreal area. Adolescents of one school were exposed to the DeStress for Success Program while adolescents from the other school served as controls. Salivary cortisol levels and depressive symptomatology were measured before, immediately after as well as 3 months after exposure to the program. Measures of negative mood were obtained at baseline in order to determine whether adolescents starting high school with specific negative moods were differentially responsive to the program. The results show that only adolescents starting high school with high levels of anger responded to the intervention with a significant decrease in cortisol levels. Moreover, we found that adolescents who took part in the intervention and showed decreasing cortisol levels following the intervention (responders) were 2.45 times less at risk to suffer from clinical and subclinical depressive states three months post-intervention in comparison to adolescents who showed increasing cortisol levels following the intervention (nonresponders). This study provides the first evidence that a school-based program on stress is effective at decreasing cortisol levels and depressive symptomatology in adolescents making the transition to high school and it helps explain which adolescents are sensitive to the program and what are some of the characteristics of these individuals.

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Depressive symptoms and memory impairments are associated with heightened stress hormone levels during aging. A factor that is related to memory deficits during aging is internalized negative aging stereotypes; the idea people have about the process of aging. In this study, we assessed the associations between internalized negative aging stereotypes, depressive symptoms, subjective and objective memory assessments, and cortisol concentration among older adults. Forty older adults aged between 58 and 85 years (18 females and 22 males; mean age ± SD: 71.25 ± 8.80 years) were assessed in this study. Measures of internalized negative aging stereotypes, depressive symptoms, and both subjective and objective memory performance were assessed. Salivary samples were obtained for measurement of cortisol concentration. Stepwise linear regressions were executed in our main analyses. Internalized negative aging stereotypes were associated with increased depressive symptoms and subjective memory complaints. No significant differences were observed for objective memory performance, or cortisol concentration. Internalized negative aging stereotypes are associated with increased depressive symptomatology and subjective complaints of memory; however, they do not predict increased cortisol concentration nor objective memory performance during aging. These results indicate that the mechanism underlying the association between internalized negative aging stereotypes and cognitive impairments may not be related to dysregulations of cortisol secretion among older adults.

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A major variant of myocilin (MYOC) [TIGR/MYOC mt.1 (-1000 C/G)], present in the gene's promoter, is found to be associated with more rapid progression of the glaucoma disease state. Time-to-event analyses using the Cox proportional hazards model produced substantial statistical evidence that this TIGR/MYOC mt.1(+) variant accelerates worsening for both optic disc and visual field measures of disease progression. These analyses were based on evaluations of 147 patients with primary open-angle glaucoma (POAG) over 35 years of age with an average follow-up of approximately 15 years. Our analyses showed that there are independent effects of the variant on disease progression, taking into account other relevant disease-related baseline risk factors, including age, family history, initial drug treatment, initial surgical treatment, diabetes, gender, myopia, and initial disease severity. The finding that a TIGR/MYOC mt.1(+) determination provided a strong marker for glaucoma progression, above and beyond the other baseline risk factors, suggests a clinical utility in testing for this promoter genotype.

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OBJECTIVE: To examine the usefulness of a test for prostate specific antigen (PSA) to predict survival in hormonally treated patients with metastatic prostate cancer. PATIENTS AND METHODS: The study comprised 49 patients (mean age 72 years, SD 6) who underwent orchidectomy for metastatic prostate cancer. PSA was measured before orchidectomy and after 6 months, and the absolute, differential and proportional decreases calculated. A Cox proportional hazards regression model, which controlled for patient age, tumour (Gleason) grade and the number of skeletal metastases, was then used to evaluate these estimates of PSA as predictors of survival. RESULTS: The 6-month proportional decrease in PSA from the pre-operative level was the most accurate predictor of patient survival (P = 0.006) after hormonal therapy for metastatic prostate cancer. CONCLUSION: This information may help to direct appropriate patients to new and experimental therapies for metastatic disease.

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Previous studies have shown that osteoinduction is inhibited when demineralized bone powder (DBP) is implanted within 48 hours of local irradiation (i.e., when the acute effects of radiation injury are present). This study sought to determine whether normal osteoinduction can proceed if the implantation of DBP is delayed until 21 days postirradiation. At 21 days, the acute effects of radiation injury are likely to have subsided, but the long-term effects have not yet appeared. Twenty-eight-day-old rats were administered a radiation dose of either 7 or 20 Gy over a localized area of one thigh. The contralateral, nonirradiated thigh served as a control. Demineralized bone powder was subcutaneously implanted 21 days later. Subcutaneous pellets were retrieved at various intervals thereafter (up to Day 45) and were histologically graded for evidence of osteoinduction. No difference in osteoinduction was detected at any time interval in pellets from the 7-Gy-treated sites, compared with controls. Pellets from the 20-Gy-treated sites, however, demonstrated significantly a lower osteoinductive response at each interval. These latter pellets showed small scattered areas of osteoinduction and reduced formation of marrow elements. Thus, although osteoinduction proceeds normally when the implantation of DBP is delayed for 21 days after irradiation with 7 Gy, this is not the case when 20 Gy are administered. Given the absence of gross impairment of tissue vascularity in irradiated sites, it is possible that inhibition of osteoinduction after higher doses of radiation results from permanent damage to mesenchymal precursor cells.

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Pharmacological effects of recombinant human tumor necrosis factor alpha (TNF) were studied in a mouse fibrosarcoma model using magnetic resonance imaging enhanced with a macromolecular contrast agent, albumin(gadolinium-diethylenetriamine pentaacetic acid)35. TNF was administered i.v. in a dose of 150 micrograms/kg, 60 to 80 min prior to imaging. Contrast-enhanced and nonenhanced magnetic resonance images of TNF-treated (n = 10) and untreated (n = 8) Meth A fibrosarcomas were obtained at 2.0 Tesla using T1-weighted spin-echo pulse sequences. Serial images spanning an interval of 60 to 120 min after TNF administration showed that the TNF-treated tumors enhanced significantly more overall than did untreated tumors (43% versus 31%). The most marked differential tumor enhancement was observed in the tumor rim (59% versus 40%). Nontumorous tissue, including muscle and brain, revealed no significant enhancement differences between TNF-treated animals and controls. The observed tumor enhancement corresponded strongly with Evans blue staining; the TNF-treated tumors stained deep blue, while untreated tumors and normal tissues observed did not stain. The different enhancement and Evans blue staining patterns between TNF-treated tumors and untreated tumors are attributed to TNF-induced changes in tumor capillary integrity. The data indicate that TNF effects on tumors include an increased capillary permeability for macromolecules at early times after administration. The ability to detect changes in capillary permeability in vivo using contrast-enhanced magnetic resonance imaging may prove to be clinically useful to monitor tumor response to TNF.

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A cohort of 129 infants with birth weights less than or equal to 1250 gm was followed for more than 4 1/2 years (mean +/- SD: 60 +/- 10 months) to determine the independent effects of two medical risk factors--intracranial hemorrhage and severe chronic lung disease--and a parenting risk factor (abuse or neglect) on neurodevelopmental outcome. In infants without any intracranial hemorrhage or parenting risk factors, severe chronic lung disease was not related to neurologic or cognitive outcome. Infants with increasing grades of intracranial hemorrhage had increasing rates of neurologic and cognitive abnormalities. However, the factor associated with the highest incidence of later abnormality was the parenting risk factor. We conclude that infants with medical risk factors may have additional social risk factors, and that both of these influences must be considered in an examination of the long-term sequelae of neonatal complications.

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Forty clones of Leishmania major were derived by direct plating from lesions and from cultures of recent isolates, followed by plating as well as by additional limit dilution in some. The parental strains originated from and represented three geographical areas in each of which a distinct electrophoretic type of the enzyme 6-phosphogluconate dehydrogenase (6PGD) is found. Each clone was characterized in terms of its virulence in Sabra mice, morphology, serotype, enzyme electrophoretic profile based on 11 enzymes, and kinetoplast DNA endonuclease restriction pattern. All the clones showed a similar virulence in the mice and similar polymorphism in fresh drops of living cultures and in Giemsa-stained preparations. Ten clones from the Jordan Valley were all serotype A1, 15 clones from the Arava were all A1Bz--confirming the mixed serological nature of parasites from this region, 11 of the 20 clones from the western Negev-eastern Sinai included a new A subserotype, and 9 were A1. Generally, the geographical separation of the 6PGD variants was upheld. Two of the Jordan Valley clones were similar to those of the western Negev. On two occasions, different enzyme types were isolated from the same individual, in one case from the same lesion. All clones from the western Negev were alike and similar to the type previously found in that region. The situation in the Arava was more complicated, since clones representative of all three regional types were found. In cases where the first two types were found, the clones and their parental strains were similar. However, one parental culture yielded three clones that resembled the reference strain for the Jordan Valley and two which resembled that of the western Negev. In one of these cases, two dissimilar clones originated from the same lesion. One aberrant clone from the western Negev was variant for nucleoside hydrolase. The kinetoplast DNA of each clone was distinct but relatively complicated, which made differentiation of these regional types difficult. However, clones from the same area displayed more similarity to each other than to those of other regions, implying a closer genetic relationship.

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We retrospectively studied the nuclear RNA content in uveal melanomas with known, long-term follow-up. Thirty patients had spindle cell melanomas, 25 had mixed cell tumors, and 9 had epithelioid cell neoplasms. Epithelioid cell types had a higher nuclear RNA content compared to mixed or spindle cell types (p less than 0.05). Using the Cox proportional hazards model, the nuclear RNA content appeared to be an independent prognostic indicator in uveal melanomas, and an increased nuclear RNA content was associated with a worse prognosis (p = 0.001).

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The value of ambulatory systolic blood pressure as a predictor of the development of cardiovascular complications was investigated in a sample of 761 hypertensive patients who had undergone ambulatory blood pressure monitoring and who were followed for an average of 5.5 years. Of the 695 patients without prior cardiovascular events at entry into the study, 11% subsequently experienced an event during the follow-up period (up to 10 years) compared to 48% of the 102 patients with a prior cardiovascular event. For each patient, a 'predicted' ambulatory systolic blood pressure was calculated, using the patient's office systolic blood pressure and the equation derived from regressing ambulatory on office blood pressure for the entire sample. By subtracting the predicted from the observed ambulatory pressure, a 'residual' ambulatory systolic blood pressure was derived for each patient, as a measure of that portion of the ambulatory pressure that could not be predicted from the office pressure. We used a Cox proportional hazards model to analyse the independent effect of each of the following patient characteristics at entry on the occurrence of subsequent cardiovascular events: sex, age, ECG evidence of left ventricular hypertrophy, hypertensive retinopathy, ambulatory systolic blood pressure, office systolic blood pressure, residual ambulatory systolic blood pressure and subsequent drug therapy. In both groups, with and without a prior cardiovascular event, women, younger patients and those with lower residual ambulatory systolic blood pressure tended to have longer periods of survival without new cardiovascular events. In the group without prior cardiovascular events, a lower office systolic blood pressure and the absence of advanced ECG evidence of left ventricular hypertrophy were also independently predictive of longer event-free survival.(ABSTRACT TRUNCATED AT 250 WORDS)

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Ocular infection with Chlamydia trachomatis, whether of genital or endemic trachoma origin, usually produces diffuse infiltration and swelling of the scleral limbus, grey infiltrates of the corneal limbus, and superficial extension of vessels onto the corneal limbus. In genitally transmitted C. trachomatis infections, subepithelial infiltrates have been reported as well. In classic endemic trachoma, limbal changes also include limbal follicles which resolve, leaving Herbert's peripheral pits, and an extensive vascular pannus. To evaluate the limbal changes in trachoma, follow-up studies were done in 1986-1987 in a group of 213 children originally seen between 1969-1972. Pannus formation occurred at a much earlier age than conjunctival scar formation and was an excellent predictor of later severe conjunctival scarring. The evidence from this study suggests that the mechanisms for corneal pannus formation from the limbus are quite different from those for scarring of the conjunctiva.

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A system was developed to measure the hydraulic conductivity of cultured monolayers of human trabecular meshwork (HTM) cells. By optimizing the cell growth conditions and evaluating a number of filter supports, confluent HTM cells in single layers were obtained for measurement of hydraulic conductivity. The HTM monolayers had hydraulic conductivities of 0.3-2.0 microliters/min/mm Hg/cm2 measured at near-physiological flow rates. Evaluations of cytochalasin B (CB) effects on the hydraulic conductivity of our HTM monolayers revealed that CB (10(-6) to 10(-5) M) caused a dramatic dose-related increase in conductivity within 10 to 30 min, which parallels CB effects on outflow facility in vivo. Morphologic observations show that the increase in hydraulic conductivity was accompanied by a retraction of the trabecular cells and widening of the intercellular spaces. Our findings suggest that growth of HTM cells on filter supports can provide a useful in vitro system to study the regulation of aqueous outflow.

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Using linear logistic regression, six factors were identified as important predictors of risk of DST sensitization in a group of 195 patients. Factors increasing the risk were: percent panel reactive antibody (PRA), previous transplants, and pregnancy; those decreasing the risk were HLA antigens matched, third-party blood transfusions, and Imuran administration. From this analysis, the magnitude of the effect of each factor on the risk of sensitization was obtained. An equation was then obtained that can be used to compute an estimated probability of sensitization (PS) for each patient. As a test of predictive ability of the model, the PS was calculated for 66 patients in an independent patient group. These observations were arranged according to the estimated probability and then divided into intervals of risk. Overall, for each interval, a very high level of agreement was found between the predicted and actual number of sensitized patients. A total of 16.13 patients were predicted to become sensitized and 17 actually did.

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We prospectively studied the age-related changes of the visual fields obtained from a selected group of 25 normal patients. The OCTOPUS automated perimeter was used to test both eyes of each patient using Program 32. We calculated the mean threshold sensitivity, volume, and surface area of the visual field and measured a linear decline with age for all three characteristics. The age-related decline in threshold sensitivity and the SE of this decline increased with eccentricity from fixation. Sensitivity declined approximately twice as rapidly at 30 degrees eccentricity as it did at fixation. The general decline in sensitivity of the visual field and the increased rate of decline with eccentricity may be related to a functional or anatomic loss of photoreceptors, ganglion cells, and higher structures.

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The presence of a layer of abnormal material in Descemet's membrane in eight keratoplasty specimens served as a marker to determine whether Chandler's syndrome, Essential Iris Atrophy, and the Cogan-Reese syndrome are congenital or acquired conditions. In all eight cases of the ICE syndrome, a pattern of membrane deposition was observed, which typifies acquired disorders: a completely normal prenatal layer and both normal and abnormal portions of the postnatal layer. The thickness of the membrane deposited before the onset of abnormal secretion was used to estimate a time span for possible ages at which abnormal secretion began. The estimated age intervals for all diseased specimens had their lower limits in the postnatal period. Thus, these results led us to the conclusion that abnormal Descemet's membrane first appeared in postnatal life, years before clinical recognition of disease. The possibility of a viral etiology for this unilateral endotheliopathy resulting in an altered Descemet's membrane is discussed.

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We correlated predicted radiation distributions in 29 patients with uveal melanoma (treated with 5,000 to 8,000 rads of helium ion therapy) with fundus photography and visual field deficits. The tumor was entirely within the treatment region in all patients. The fraction of the predicted high-dose and low-dose regions corresponding with an absolute scotoma was fitted by a linear regression model (r2 = .721) with three independent variables: dose region, initial condition, and time since therapy. The defect in the maximum-dose region increased at an average rate of 0.270/year. This differed (P = .002) from the rate in the penumbra region: (0.104/year). The rate in the penumbra differed (P = .01) from that in the predicted low-dose region, where scotoma did not increase with time. The pattern and time course of visual field loss in the different radiation dose regions tended to support the conclusion that isodose calculations are accurate. The data were consistent with the hypothesis that visual loss secondary to irradiation results primarily from radiation vasculopathy and not from direct damage to photoreceptors or ganglion cells. Development of an absolute scotoma may require a dose in excess of 5,000 rads.

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This report details the development of an empirical suicide risk scale for adults hospitalized due to a depressive or suicidal state. The authors studied 2,753 such subjects prospectively regarding 101 psychosocial variables. In a 2-year follow-up, 136 (4.94%) of the subjects had committed suicide. Rigorous statistical analysis, including a validation procedure, identified 15 variables as significant predictors of suicidal outcome. These were translated into a paper-and-pencil scale that gives an estimated risk of suicide within 2 years. Such an instrument can provide a valuable supplement to clinical judgment and a quantitative expression of suicide risk.

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The origin, growth in thickness, and differentiation of Descemet's membrane was studied by light, electron microscopic, morphometric, and statistical methods in 67 specimens from 12 weeks of gestation to 98 years. Descemet's membrane is formed by three major processes: growth in thickness during the prenatal period, prenatal differentiation into a striated basement membrane, and growth in thickness during the postnatal period. The initial step is the synthesis of an ordinary basement membrane, which is very thin and quite different in appearance from the adult Descemet's membrane. Growth of the prenatal Descemet's membrane then proceeds by deposition of a series of similar "membrane units," which are stacked to form a lamellar structure consisting of at least 30 layers by the end of gestation. Second, during prenatal life, differentiation of the membrane leads to the formation of a striated structure through the gradual addition of short and thin cross-linking bridges separated by 110-nm intervals that are disposed in a plane perpendicular to the lamellae. The third process occurs in postnatal life when the membrane continues to grow in thickness by deposition of a nonstriated, nonlamellar material posterior to the striated prenatal layer. Regression analysis suggests that prenatal growth proceeds at a rapid but variable rate best described by a "sigmoid-like" function of age. Postnatal growth, in contrast, proceeds in a predominantly exponential manner but at a slower pace than in the prenatal period. The low variability and large size of our set of measurements make these data especially useful for comparisons with pathologic specimens.

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