Origins of the Iberomaurusian in NW Africa: new AMS radiocarbon dating of the Middle and Later Stone Age deposits at Taforalt Cave, Morocco.

Recent genetic studies based on the distribution of mtDNA of haplogroup U6 have led to subtly different theories regarding the arrival of modern human populations in North Africa. One proposes that groups of the proto-U6 lineage spread from the Near East to North Africa around 40-45 ka (thousands of years ago), followed by some degree of regional continuity. Another envisages a westward human migration from the Near East, followed by further demographic expansion at ∼22 ka centred on the Maghreb and associated with a microlithic bladelet culture known as the Iberomaurusian. In evaluating these theories, we report on the results of new work on the Middle (MSA) and Later Stone (LSA) Age deposits at Taforalt Cave in Morocco. We present 54 AMS radiocarbon dates on bone and charcoals from a sequence of late MSA and LSA occupation levels of the cave. Using Bayesian modelling we show that an MSA non-Levallois flake industry was present until ∼24.5 ka Cal BP (calibrated years before present), followed by a gap in occupation and the subsequent appearance of an LSA Iberomaurusian industry from at least 21,160 Cal BP. The new dating offers fresh light on theories of continuity versus replacement of populations as presented by the genetic evidence. We examine the implications of these data for interpreting the first appearance of the LSA in the Maghreb and providing comparisons with other dated early blade and bladelet industries in North Africa.

Neanderthal exploitation of marine mammals in Gibraltar.

Two coastal sites in Gibraltar, Vanguard and Gorham's Caves, located at Governor's Beach on the eastern side of the Rock, are especially relevant to the study of Neanderthals. Vanguard Cave provides evidence of marine food supply (mollusks, seal, dolphin, and fish). Further evidence of marine mammal remains was also found in the occupation levels at Gorham's Cave associated with Upper Paleolithic and Mousterian technologies [Finlayson C, et al. (2006) Nature 443:850-853]. The stratigraphic sequence of Gibraltar sites allows us to compare behaviors and subsistence strategies of Neanderthals during the Middle Paleolithic observed at Vanguard and Gorham's Cave sites. This evidence suggests that such use of marine resources was not a rare behavior and represents focused visits to the coast and estuaries.

Cortisol kinetics in elderly women with persistently high cortisol concentrations after proximal femur fracture.

OBJECTIVES: Elderly women with proximal femur fracture show abnormal persistence of increased cortisol concentrations, which could contribute to the high morbidity associated with this injury. Two weeks after injury, the authors found substantially increased urinary free cortisol excretion, which usually reflects the integrated concentration of free (bioactive) cortisol in plasma. However, there was a proportionally smaller increase in cortisol production rate. The authors have now tested the hypothesis that this was caused by a decreased metabolic clearance rate (MCR) rather than increased renal clearance, because the latter but not the former would invalidate free cortisol excretion as an index. SETTING: Orthopaedic wards in a teaching hospital. PATIENTS: Thirteen women aged seventy-one to ninety-two years who had sustained a proximal femur fracture approximately two weeks earlier were compared with ten healthy women aged sixty-seven to eighty-three years. These subjects are similar to those in the authors' previous study. MAIN OUTCOME MEASUREMENTS: The authors used single injections of [3H] cortisol to measure its MCR and estimated hepatic blood flow with indocyanine green. RESULTS: The patients with hip fractures had higher plasma cortisol concentrations than did the healthy subjects, as expected. Cortisol MCR was approximately 20 percent lower in the patients, and estimated hepatic blood flow was approximately 35 percent lower in the patients. Analysis of covariance showed that the difference in MCR was the result of the small difference in age between the groups rather than to injury per se. CONCLUSIONS: A lower cortisol MCR in the patients with hip fractures explains the authors' previous results and validates urinary free cortisol excretion as an index. The data suggest a roughly threefold mean increase in plasma cortisol bioactivity two weeks after hip fracture.

Disrupted cortisol-ACTH relationships in elderly women given corticotrophin-releasing hormone two weeks after proximal femur fracture.

OBJECTIVE: In elderly women with hip fractures plasma cortisol is persistently higher than in healthy elderly women, possibly causing undesirable catabolic effects. A lack of corresponding changes in plasma ACTH or in the cortisol response to exogenous ACTH has prompted us to study cortisol-ACTH relationships after giving corticotrophin-releasing hormone (CRH) to such subjects. SUBJECTS: Seventeen women aged 70-90 years who had sustained a hip fracture about two weeks previously were compared with 19 healthy women aged 68-85 years. MEASUREMENTS: 100 microg CRH was injected into each subject and ACTH and cortisol concentrations were measured at intervals for 90 minutes beforehand and 180 minutes afterwards. The concentrations of vasopressin and various cytokines and related peptides were also measured during the baseline period. RESULTS: Under baseline conditions plasma cortisol was higher and plasma ACTH lower in the injured patients than in the healthy subjects. The patients showed smaller incremental ACTH and cortisol responses to CRF but because of the higher baseline value the peak cortisol concentration was enhanced. A strong correlation between the cortisol and ACTH responses in the healthy subjects was completely lost in the patients and the slope of the ACTH-cortisol dose-response relationship varied greatly between individuals, with no overall increase. The concentrations of vasopressin, interleukin-1 receptor antagonist and soluble tumour necrosis factor receptors were higher in the patients but did not correlate with the responses to CRH. CONCLUSIONS: The results are not consistent with increased sensitivity to ACTH and suggest an independent stimulus to the adrenals of hip-fracture patients. Its identity is unknown as the non-ACTH stimuli proposed hitherto are reported to enhance sensitivity to ACTH.

The effect of aging on the metabolic clearance rate and distribution of cortisol in man.

Previous studies of cortisol kinetics in old people have been flawed. All but one used a large dose of unlabelled cortisol, which will itself alter the kinetic parameters, and in none was metabolic clearance rate (MCR) calculated. We have, therefore, injected [(3)H]cortisol into men aged 20-38 and healthy (screened) men and women aged 63-83 years and followed its disappearance from the circulation for 3 h. In all three groups the disappearance curves corresponded closely to a double exponential, with half-lives of around 5 and 65 min. A two-pool model was assumed, one being purely a side-pool. The initial and total volumes of distribution and the MCR, but not the clearance rate for exchange between the two pools, tended to be lower in the elderly men than in the young; only the difference in total volume was significant. All these parameters were lower in the elderly women than in the elderly men. We conclude that any decline in cortisol MCR and related kinetic parameters with aging in men is small compared with variation from other sources. These parameters are lower in elderly women than men, in line with a reported sex difference in MCR in young subjects.

Sensitivity of mononuclear leucocytes to glucocorticoids in elderly hip-fracture patients resistant to suppression of plasma cortisol by dexamethasone.

OBJECTIVE: Elderly women with proximal femur fracture show a prolonged increase in plasma cortisol, which could have undesirable catabolic effects. Suppression of cortisol by dexamethasone is impaired, suggesting resistance to glucocorticoid effects at feedback inhibitory sites. We therefore wished to find out whether peripheral glucocorticoid sensitivity is normal. DESIGN: Peripheral blood mononuclear leucocytes were used as a model tissue. Blood samples were taken from elderly women about 2 weeks after hip fracture and from elderly control women. Each patient was then given 1 mg dexamethasone at 2300 h followed by further sampling at 0800 and 1600 h the next day. METHODS: Glucocorticoid-receptor binding parameters were measured by incubating whole cells with [3H]dexamethasone for 2 h at 37 degrees C. Inhibition of cell proliferation by dexamethasone was assessed by addition of [3H]thymidine to cells cultured for 65 h with concanavalin A. Cortisol and dexamethasone concentrations were measured in the dexamethasone suppression test. RESULTS: As expected, the hip-fracture patients had raised morning cortisol concentrations and impaired suppression by dexamethasone. The cells of the patients had similar numbers of glucocorticoid receptors to those of the control subjects but higher values for Kd (i.e. a lower binding affinity). The cells of the patients incorporated less [3H]thymidine than the control cells in the absence of dexamethasone. The percentage inhibition by a saturating concentration of dexamethasone was unchanged but the concentration giving half-maximal inhibition was decreased (sensitivity was increased) at the higher of the two concanavalin A concentrations used. CONCLUSIONS: These experiments in mononuclear leucocytes give no evidence of peripheral resistance to glucocorticoids in hip-fracture patients with impaired suppression of cortisol by dexamethasone.

Time course of the early pituitary-adrenal and metabolic responses to accidental injury.

We have made serial measurements of the plasma adrenocorticotrophic hormone (ACTH), cortisol, glucose, lactate, glycerol, nonesterified fatty acid (NEFA), and beta-hydroxybutyrate concentrations in 14 recently injured patients. We took 6 to 9 blood samples at about 20-minute intervals from each patient within the first 3 hours after accidental injury of moderate severity (Injury Severity Score of 9 to 13). Plasma ACTH varied greatly both with time and between patients; in the majority, it fell throughout the sampling period and in the others, the pattern varied. The changes in plasma cortisol were mostly appropriate to those in ACTH. Plasma glucose and glycerol did not change systematically with time. In contrast, plasma lactate fell, and plasma NEFA, beta-hydroxybutyrate, and the NEFA:glycerol ratio rose, throughout the sampling period. Analysis of variance for these data showed that time after injury made a contribution that was highly significant, although smaller than that arising from differences between patients.

Cortisol production rate and the urinary excretion of 17-hydroxycorticosteroids, free cortisol, and 6 beta-hydroxycortisol in healthy elderly men and women.

BACKGROUND: Although many workers have tested adrenal function in the elderly, few have studied the effect of aging on cortisol production rate or urinary free cortisol or 6 beta-hydroxycortisol excretion, and none have published comparisons of these variables between old people of defined health status and young people. METHODS: We have measured cortisol production rate and the urinary excretion of free cortisol, 6 beta-hydroxycortisol, 17-hydroxycorticosteroids (Porter-Silber chromogens) and creatinine in elderly men and women screened by the SENIEUR protocol and in young men; 17-hydroxycorticosteroid and 6 beta-hydroxycortisol excretion were also measured in young women. The period of measurement was 24 h or, usually, 48 h. RESULTS: Only 6 beta-hydroxycortisol excretion was affected by aging; it was lower in the elderly men and women than in their younger counterparts. Urinary free cortisol excretion was lower in the elderly women than in the elderly men. There were no significant differences between groups in cortisol production rate or 17-hydroxycorticosteroid excretion. Excretion and (over the first 24 h) clearance of creatinine were lower in the old women than in the old men. The cortisol-related variables tended to be positively correlated with each other and with the relevant creatinine-related variables in the elderly subjects; over the first but not the second 24 h, most of the correlations were significant in the men and women combined. CONCLUSIONS: With the exception of 6 beta-hydroxycortisol, the data agree with measurements of plasma cortisol and the results of adrenal function tests in showing little change in hypothalamic-pituitary-adrenal function with aging in healthy people.

Increased rates of cortisol production and urinary free cortisol excretion in elderly women 2 weeks after proximal femur fracture.

Cortisol production rate and urinary free cortisol excretion have been measured in healthy elderly women and elderly women about two weeks after upper femur fracture. Plasma cortisol was determined mid-morning, at the start of urine collection. All three variables were higher in the injured patients than in the control subjects. Urinary free cortisol excretion showed the greatest rise and was correlated with cortisol production rate in the patients. In the control subjects there was no correlation and nearly all the points fell below the regression line for the injured patients, indicating that urinary free cortisol excretion rose in relation to cortisol production rate after injury. Measurement of creatinine clearance showed that this was not due to an increased glomerular filtration rate, and a possible explanation is decreased metabolic clearance of cortisol. Plasma cortisol was not significantly correlated with either cortisol production rate or urinary free cortisol excretion.

Factors influencing cortisol-adrenocorticotrophin relationships in elderly women with upper femur fractures.

In elderly women with proximal femur fractures, plasma cortisol levels are still elevated 2 weeks after injury. We have now measured the concentrations of adrenocorticotrophin (ACTH) and its precursor peptides (pro-opiomelanocortin plus pro-ACTH) in blood samples obtained in the morning and afternoon from such patients and from old and young control subjects. In healthy subjects, aging had no effect on these variables. Compared with healthy elderly women, the injured women had elevated cortisol but not ACTH concentrations; at both times of day their precursor peptide concentration was increased but probably not enough to affect cortisol secretion substantially. There were no correlations between the concentrations of cortisol, ACTH, and precursor peptides. We have also studied adrenocortical sensitivity after giving dexamethasone overnight. The cortisol responses to graded doses of ACTH did not differ between injured and healthy elderly women, suggesting that their higher cortisol concentrations were the results of stimuli acting independently of ACTH.

Ageing and the sensitivity of the adrenal gland to physiological doses of ACTH in man.

Healthy men and women aged 19-38 or 67-83, in whom endogenous ACTH secretion was suppressed with dexamethasone, were given successive injections of 60 ng, 150 ng and 250 micrograms ACTH(1-24) at hourly intervals, and blood samples for measurement of plasma cortisol were taken every 10 min. The response to each injection was taken as the increase in cortisol concentration 20 min later, when there was a peak with the lower doses, with allowance for disappearance of cortisol produced after the previous injection. On average, the responses to 60 and 150 ng ACTH were about 0.4 and 0.7 respectively of the response to 250 micrograms. There were no consistent effects of age or sex on any index of adrenocortical sensitivity or responsiveness, but some groups showed isolated differences from both their age- and sex-matched counterparts: the response to 60 ng ACTH was low in young men, maximal responsiveness was low in elderly men and the slope of the dose-response curve was high in elderly women. In most of the elderly subjects, plasma ACTH was determined separately under normal conditions. It was negatively correlated with the cortisol responses to 60 and 150 ng ACTH, suggesting that differences in adrenal sensitivity between subjects contribute to the variability of plasma ACTH.

Adrenal function after upper femoral fracture in elderly people: persistence of stimulation and the roles of adrenocorticotrophic hormone and immobility.

Previous work has shown persistent elevations in plasma cortisol concentration following upper femur fracture in elderly people. To investigate this phenomenon further, we measured plasma cortisol and adrenocorticotrophin (ACTH) and performed overnight dexamethasone suppression tests in carefully characterized patients and controls (mobile and immobile). There was no difference in cortisol or ACTH, either basally or after dexamethasone, between the mobile and immobile controls. At 2 and 8 weeks after injury, basal plasma cortisol was significantly higher than in either control group and was not related to an index of the patients' mobility potential. The ACTH concentrations also tended to be raised after injury, but the differences in concentration between injured and control subjects did not reach statistical significance. At both 2 and 8 weeks after injury, the post-dexamethasone cortisol concentration was significantly higher in the fracture patients, particularly the least mobile. Our results show that the elevation in plasma cortisol concentration in elderly femur-fracture patients, which may persist for at least 8 weeks after injury, is not explained by immobility and is probably mediated by an increased central drive to the hypothalamic-pituitary-adrenal axis.

The neuroendocrinology of physical injury.

Physical injury of any sort--accidental injury, burns or elective surgery--provokes an immediate neuroendocrine response. Neural input arising from the cerebral cortex, damaged tissues and receptors detecting fluid loss leads to increased secretion of ACTH, growth hormone, prolactin and vasopressin from the pituitary, and to a general activation of the sympathetic nervous system, with rises in adrenaline and noradrenaline concentrations. Secondary changes include stimulation of cortisol and aldosterone and inhibition of insulin and somatomedin secretion. The glucagon concentration and plasma renin activity may also be increased, either immediately or after a delay. The duration of these responses generally depends upon the severity of the injury and differs considerably between hormones, for reasons that are not understood. The only endocrine changes consistently seen at later times after trauma are an increase in insulin secretion, which supersedes the initial suppression, and decreases in the concentrations of T3 and gonadal steroids. Some of the changes in steroid, thyroid and pancreatic hormones differ temporally or even qualitatively from those of their usual stimuli and are unexplained. The initial neuroendocrine response to injury can be construed as playing a defensive role, but the function of the later changes is not understood; it seems likely that they are adaptive in nature, but the scope for therapeutic intervention remains unclear.

Relationships among plasma cortisol, adrenocorticotrophin, and severity of injury in recently injured patients.

When samples were taken within 2 hr of accidental injury, plasma cortisol levels increased with injury severity score (ISS) in patients with minor and moderate injuries (ISS, 1-12) but decreased at higher ISS. Radioimmunoassay of adrenocorticotrophin (ACTH) showed very variable plasma concentrations at all ISS ranges. Like cortisol, ACTH increased with ISS up to a score of about 13, but it thereafter plateaued, and in patients with severe injuries plasma cortisol fell in relation to ACTH as well as in absolute terms. This suggested that although ACTH secretion was generally far from maximal the relatively low cortisol concentrations in the most severely injured were at least partly due to a poor response of the adrenal cortex to ACTH. In patients who presented late (more than 2 hr after injury) plasma cortisol levels were more variable and more strongly related to ACTH than at shorter times after injury. The variability of cortisol also increased with age. Patients with severe head injuries had cortisol and ACTH concentrations similar to those without head injuries but with a similar ISS from injuries in other parts of the body.

Application of high-performance liquid chromatography to the measurement of cortisol secretion rate.

After administration of [3H] cortisol, the specific radioactivity of the urinary cortisol metabolites is determined by chemical conversion of the 17-hydroxycorticosteroid conjugates to 17-ketosteroids, extraction with Sep-Pak C18 cartridges, derivatisation with 2,4-dinitrophenylhydrazine and isocratic reversed-phase high-performance liquid chromatography. This allows on-line measurement of ultra-violet absorbance; fractions are collected and 3H is measured by scintillation counting. Alternatively extraction and chromatography are done after enzymic hydrolysis of the steroid conjugates, and the major metabolites are determined colorimetrically in the fractions. The results from the two methods were consistent with each other and with published data.

Movement of albumin between plasma and tissues after limb ischaemia in the rat.

During the first few hours after limb ischaemia in the rat, the plasma protein concentration does not fall despite substantial compensatory fluid movement into the circulation. We have therefore attempted to find out whether this fluid is accompanied by albumin. Rats injected the previous day with 125I-labelled albumin were subjected to 4-h bilateral hind-limb ischaemia. The uptake of label by the hind limbs and the changes in plasma albumin and 125I concentrations were measured during the subsequent 3 h. The calculated concentration of albumin in the fluid moving into the injured tissues was similar to the measured concentration in the oedema fluid and about half the plasma albumin concentration, which fell slightly. The accumulation of albumin in the injured legs almost balanced the loss from the circulation and there was little or no mobilisation of albumin from uninjured tissues. The data were consistent with early compensation largely by transcapillary refilling.

Persistence of high plasma glucose, insulin and cortisol concentrations in elderly patients with proximal femoral fractures.

Plasma glucose, insulin and cortisol concentrations were measured in elderly patients with femoral neck fractures. The results have been compared with those in younger injured patients as well as younger and elderly control subjects. There was a prolonged elevation of plasma glucose, insulin and cortisol concentrations after femoral neck fractures, in contrast to a rapid return to normal in younger injured patients. Comparison with the control groups suggested that this might reflect the effects of immobility rather than of age or of injury per se. The pattern of insulin resistance together with a high cortisol concentration could hinder recovery.