Behavioral effects of pubertal anabolic androgenic steroid exposure in male rats with low serotonin

The goal of this study was to assess the interactive effects of chronic anabolic androgenic steroid (AAS) exposure and brain serotonin (5-hydroxytryptamine, 5-HT) depletion on behavior of pubertal male rats. Serotonin was depleted beginning on postnatal day 26 with parachlorophenylalanine (PCPA 100 mg/kg, every other day); controls received saline. At puberty (P40), half the PCPA-treated rats and half the saline-treated rats began treatment with testosterone (T, 5 mg/kg, 5 days/week). Behavioral measures included locomotion, irritability, copulation, partner preference, and aggression. Animals were tested for aggression in their home cage, both with and without physical provocation (mild tail pinch). Brain levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were determined using HPLC. PCPA significantly and substantially depleted 5-HT and 5-HIAA in all brain regions examined. Chronic T treatment significantly decreased 5-HT and 5-HIAA in certain brain areas, but to a much lesser extent than PCPA. Chronic exposure to PCPA alone significantly decreased locomotor activity and increased irritability but had no effect on sexual behavior, partner preference, or aggression. T alone had no effect on locomotion, irritability, or sexual behavior but increased partner preference and aggression. The most striking effect of combining T+PCPA was a significant increase in attack frequency as well as a significant decrease in the latency to attack, particularly following physical provocation. Based on these data, it can be speculated that pubertal AAS users with low central 5-HT may be especially prone to exhibit aggressive behavior.     

Simultaneous measurements of cerebral blood flow by the xenon/CT method and the microsphere method. A comparison

Simultaneous measurements of cerebral blood flow have been performed in baboons to assess the correlation between the acute and invasive nondiffusible microsphere technique and the noninvasive xenon-enhanced CT method. Blood flows in small tissue volumes (approximately 1 cm3) were directly compared. The results of these studies demonstrate a statistically significant association between the two methods (P less than .001). Similar correlations were obtained by both the Kendall tau (tau) and the Spearman (r) methods. The problems and limitations of such correlations are discussed.     

Stable xenon enhanced computed tomography in the study of clinical and pathologic correlates of focal ischemia in baboons

When the lateral striate arteries of baboons are occluded, an immediate cessation of blood flow followed by a transient, minimal restitution of flow occurs in that vascular distribution. These findings are evident from serial xenon/computed tomography cerebral blood flow imaging. In our study, infarction consistently accompanied arterial occlusion for 6 hours or more. The xenon/computed tomography method provides a sensitive, noninvasive technique for examining sequential alterations of cerebral blood flow in small regions deep within the brain. This methodology for recording cerebral blood flow permits correlative studies of cerebral infarction, clinically and experimentally, and allows reasonable inferences about the probabilities of neural tissue damage.     

Aneurysms of the intracavernous carotid artery: clinical presentation, radiographic features, and pathogenesis

Thirty-seven patients with 44 intracavernous carotid artery aneurysms (ICCAAns) were seen at one institution from 1976 through 1988. Fifteen patients had multiple intracranial aneurysms and 7 had bilateral ICCAAns. Age at diagnosis ranged from 15 to 80 (median 61). Thirty patients were women. Sixteen had a history of hypertension. In 34% of patients the ICCAAns were asymptomatic at diagnosis, 36% were associated with headache, and 57% had associated signs or symptoms of mass effect including sixth nerve paresis (43%), trigeminal pain or sensory loss (32%), third nerve paresis (20%), decreased vision or visual field cut (18%), fourth nerve paresis (16%), and Horner's syndrome (7%). In 4 patients the ICCAAns ruptured, leading to subarachnoid hemorrhage in 3 and epistaxis in 1. Two patients with ICCAAns were seen with spontaneous thrombosis of the ipsilateral internal carotid artery leading to distal ischemic symptoms in 1. More than 90% of the ICCAAns were saccular. Thirty-four percent were small (less than 1 cm), 48% were large (1 to 2.5 cm), and 16% were giant (greater than 2.5 cm). The majority arose from the anterior genu of the intracavernous internal carotid artery, followed in frequency by the horizontal segment, and then the posterior genu. Magnetic resonance imaging is superior to computed tomography for diagnosing ICCAAns and is the screening procedure of choice. Angiography remains the "gold standard" for diagnosis and determining specific anatomic details necessary to plan therapy. Analyzing the radiographic anatomy of 44 ICCAAns. we conclude that theories attributing the origin of aneurysms to arterial bifurcations may be inadequate to explain the point of origin and direction of take off of up to one-fourth of ICCAAns.     

Endocranial ontogeny and evolution in early Homo sapiens: The evidence from Herto,Ethiopia

Fossils and artifacts from Herto, Ethiopia, include the most complete child and adult crania of early Homo sapiens. The endocranial cavities of the Herto individuals show that by 160,000 y ago, brain size, inferred from endocranial size, was similar to that seen in modern human populations. However, endocranial shape differed from ours. This gave rise to the hypothesis that the brain itself evolved substantially during the past ∼200,000 y, possibly in tandem with the transition from Middle to Upper Paleolithic techno-cultures. However, it remains unclear whether evolutionary changes in endocranial shape mostly reflect changes in brain morphology rather than changes related to interaction with maxillofacial morphology. To discriminate between these effects, we make use of the ontogenetic fact that brain growth nearly ceases by the time the first permanent molars fully erupt, but the face and cranial base continue to grow until adulthood. Here we use morphometric data derived from digitally restored immature and adult H. sapiens fossils from Herto, Qafzeh, and Skhul (HQS) to track endocranial development in early H. sapiens. Until the completion of brain growth, endocasts of HQS children were similar in shape to those of modern human children. The similarly shaped endocasts of fossil and modern children indicate that our brains did not evolve substantially over the past 200,000 y. Differences between the endocranial shapes of modern and fossil H. sapiens adults developed only with continuing facial and basicranial growth, possibly reflecting substantial differences in masticatory and/or respiratory function.

The brains of living humans are about three times larger than those of our closest living relatives, the great apes, and human brains exhibit marked structural differences, notably in areas involved in complex cognitive tasks such as language (1). When and how the characteristic features of the human brain evolved, however, is a matter of ongoing discussion because fossil endocasts—the shapes and sizes of natural or virtual fillings of braincases—can only partially inform about brain anatomy (2, 3). Brain size can be estimated from endocranial size, brain shape from endocranial shape, and external brain structures such as sulci and gyri from their imprints on the endocranial surfaces. Fossil evidence suggests that key features of the brains of living humans, such as expanded cerebral association areas of the inferior frontal and posterior parietal lobes, evolved relatively late (<1.7–1.5 million years ago [Ma]), rather than at the beginnings of our genus Homo at approximately 2.5 Ma (4). The brains of fossil Homo younger than 1.5 Ma therefore were likely structurally similar to those of present-day humans (4). However, our brains and their surrounding braincases are now more rounded in shape (5). Indeed, endocranial globularity in combination with facial retraction is characteristic of Late Pleistocene-to-recent Homo sapiens, but rarely present in earlier fossils (4).Various hypotheses have been proposed to explain how the modern human endocranial morphology evolved and developed after the split from the last common ancestor with our close fossil relatives, the Neanderthals (5–8). Endocranial ontogeny is relatively well documented in Neanderthals, permitting inferences about brain ontogeny. Compared to present-day humans, Neanderthals had similar endocranial sizes at birth, indicating similar neonatal brain sizes. However, Neanderthals had higher postnatal endocranial (and brain) growth rates, resulting, on average, in larger adult brain sizes [but not in earlier completion of brain growth (9)]. Furthermore, tracking Neanderthal endocranial development (i.e., change in shape) from birth to adulthood suggests marked differences in brain development compared to present-day humans, either in utero (10), or during early postnatal life (11).When and how the modern human mode of endocranial and brain ontogeny evolved, however, remains an open question. This is because, on the one hand, the adult endocranial shape of recent humans is markedly different from that of Pleistocene fossil H. sapiens (5, 8); and on the other, because only few immature fossil specimens have been available with which to document endocranial ontogeny in fossil H. sapiens. The difference between fossil and recent adult H. sapiens endocranial shapes has been interpreted as evidence for developmental and structural novelties of the brain that evolved gradually over the past 200 ka (thousand years ago) probably in concert with techno-cultural innovations during the Middle to Upper Paleolithic transition (8).This hypothesis assumes that evolutionary changes in endocranial shape reflect changes in brain shape that were ultimately caused by structural changes in the brain. Endocranial shape does largely represent brain shape (12). However, this does not signify that the brain alone influences endocranial shape. Other external constraints also influence endocranial shape. Overall, evolutionary and developmental changes in endocranial shape are due not only to intrinsic changes in the brain but also to extrinsic factors such as the changing proportions of the neurocranium (the skull region enclosing the brain) relative to the viscerocranium (the face and cranial base) (7, 13). Facial size in members of the H. sapiens species lineage gradually reduced during the past 200–300 ka (14), a period during which techno-cultural changes and changes in subsistence strategy had impacts on facial size and shape as well as on masticatory function (15).Consequently, it is necessary to assess the effects of both viscerocranial and cerebral factors on changes in endocranial size and shape during both ontogeny of fossil H. sapiens and also during the past 200 ka of our evolution. Fortunately, there is now a growing sample of immature and adult fossil H. sapiens with which to investigate these relations. Key among them are the crania of a child (age at death estimated to 6–7 y, based on dental maturation patterns) and an adult from Herto, Ethiopia (14), recovered in archaeological (16) and chronostratigraphic (∼160 ka) contexts that have rendered them crucial referents in discussions about the biological evolution and behavior of early H. sapiens (17, 18). Although well-preserved, both the child (BOU-VP-16/5) and adult (BOU-VP-16/1) from Herto suffered slight but significant prerecovery taphonomic distortion that limited their initial metric characterization. To accurately compare and illuminate the evolutionary and developmental biology of fossil and recent H. sapiens, we employ newly rendered digital restorations of these two crania.We apply an evolutionary developmental approach to compare endocranial and viscerocranial growth and development between fossil and recent H. sapiens and to examine how facial size reduction affected endocranial shape in evolving H. sapiens. The human brain nearly ceases its growth around the age of 5–6 y (19) whereas the face and cranial base continue to grow. This rate transition occurs around the time when the first permanent molars (M1s) fully erupt into functional occlusion. This allows us to test the hypothesis that adult endocranial shape is influenced by viscerocranial (i.e., facial and basicranial) development.Here, we describe and illustrate our stepwise field and laboratory recovery and physical restorations of the two original Herto fossil crania (Fig. 1 and SI Appendix, Figs. S1–S14), as well as the methods used to digitally render and accurately restore them (Fig. 2 and SI Appendix, Figs. S15–S22). We then generate comprehensive metric datasets for comparative uses and apply geometric morphometric methods to quantify endocranial and viscerocranial size and shape of these key specimens. Finally, we compare them with similarly processed child and adult fossils from Skhul and Qafzeh (∼120–100 ka) and a large comparative sample spanning the evolutionary time from early Homo to recent humans.Open in a separate windowFig. 1.Discovery and restoration of the Herto adult (BOU-VP-16/1) and child (BOU-VP-16/5) crania. Adult cranium (A–F). (A) D. DeGusta examines scatter of surface cranial vault fragments of (yellow flags); (then) seasonally abandoned Herto Afar village in background. When occupied, hundreds of domestic ungulates (camels, cows, sheep, goats) cross this surface each day. View is to the west. (B) Tight concentration of cranial vault pieces indicated relatively limited scatter after recent erosional exposure. (C) Indurated sandstone cemented to the right side of the cranium obscures most bone. (D) Removal of sand and sandstone reveals the intact right side of the cranium. (E) The frontal sinus is large, with thin anterior and posterior walls. Even more fragile maxillary, ethmoidal and sphenoid bone is left encased in the hardened sandstone because it cannot be safely cleaned. (F) Right lateral view of the cranium after physical restoration. Child cranium (G–K). (G) B. Asfaw points to fragments of cranial vault. View is to the north, Central Awash Complex in background. (H) Larger cranial vault pieces indicated by yellow arrows. Other surface lag comprises indurated sandstone fragments and artifacts. Wet sieving recovered smaller pieces. (I) Recovered pieces. (J) Refitting. (K) Three-quarter view of the restored specimen. An extended set of photographs documenting the recovery and restoration procedures is provided in SI Appendix, Figs. S1–S14.Open in a separate windowFig. 2.Digital restoration of the Herto crania and their endocasts. Left: Herto adult BOU-VP-16/1. Right: Herto child BOU-VP-16/5. Crania are shown in anterior and lateral views; endocasts in posterior and lateral views. (Scale bar: 5 cm.) Details of the restoration procedure and full sets of the six standard views are provided in SI Appendix, Figs. S15–S22.     

From the Cover: Canine sexual dimorphism in Ardipithecus ramidus was nearly human-like

Body and canine size dimorphism in fossils inform sociobehavioral hypotheses on human evolution and have been of interest since Darwin’s famous reflections on the subject. Here, we assemble a large dataset of fossil canines of the human clade, including all available Ardipithecus ramidus fossils recovered from the Middle Awash and Gona research areas in Ethiopia, and systematically examine canine dimorphism through evolutionary time. In particular, we apply a Bayesian probabilistic method that reduces bias when estimating weak and moderate levels of dimorphism. Our results show that Ar. ramidus canine dimorphism was significantly weaker than in the bonobo, the least dimorphic and behaviorally least aggressive among extant great apes. Average male-to-female size ratios of the canine in Ar. ramidus are estimated as 1.06 and 1.13 in the upper and lower canines, respectively, within modern human population ranges of variation. The slightly greater magnitude of canine size dimorphism in the lower than in the upper canines of Ar. ramidus appears to be shared with early Australopithecus, suggesting that male canine reduction was initially more advanced in the behaviorally important upper canine. The available fossil evidence suggests a drastic size reduction of the male canine prior to Ar. ramidus and the earliest known members of the human clade, with little change in canine dimorphism levels thereafter. This evolutionary pattern indicates a profound behavioral shift associated with comparatively weak levels of male aggression early in human evolution, a pattern that was subsequently shared by Australopithecus and Homo.

A small canine tooth with little sexual dimorphism is a well-known hallmark of the human condition. The small and relatively nonprojecting deciduous canine of the first known fossil of Australopithecus, the Taung child skull, was a key feature used by Raymond Dart for his inference that the fossil represented an early stage of human evolution (1). However, recovery of additional Australopithecus fossils led to the canine of Australopithecus africanus to be characterized as large (compared to that of humans or “robust australopithecines”) and its morphology primitive, based on a projecting main cusp and crown structures lacking or hardly expressed in Homo (2). Later, the perception of a large and primitive canine was enhanced by the discovery and recognition of Australopithecus afarensis and Australopithecus anamensis (3–8), the latter species extending back in time to 4.2 million years ago (Ma). Although assessments of canine size variation and sexual dimorphism in Au. afarensis were hampered by limited sample sizes (9, 10), some suggested that the species had a more dimorphic canine than do humans, equivalent in degree to the bonobo (11) or to chimpanzees and orangutans (12). Initially, Au. anamensis was suggested to express greater canine dimorphism than did Au. afarensis (13, 14). However, based on a somewhat larger sample size, this is now considered to be the case with the tooth root but not necessarily its crown (15–17).Throughout the 1990s and 2000s, a pre-Australopithecus record of fossils spanning >6.0 to 4.4 Ma revealed that the canines of these earlier forms did not necessarily exceed those of Au. afarensis or Au. anamensis in general size (18–28). However, all these taxa apparently possessed canine crowns on average about 30% larger than in modern humans, which makes moderately high levels of sexual dimorphism potentially possible. Canine sexual dimorphism, combined with features such as body size dimorphism, inform sociobehavioral and ecological adaptations of past and present primates, and therefore have been of considerable interest since Darwin’s 1871 considerations (29–57). In particular, the relationship of canine size dimorphism (and/or male and female relative canine sizes) with reproductive strategies and aggression/competition levels in primate species have been a continued focus of interest (14, 33, 35–45, 49–56). Conspecific-directed agonistic behavior in primates related to mate and/or resource competition can be particularly intense among males both within and between groups (14, 44, 57). It is widely recognized that a large canine functions as a weapon in intra- and intergroup incidences of occasional lethal aggression (45, 58–61), and a large, tall canine has been shown or inferred to significantly enhance male fitness (50, 56). Hence, canine size and dimorphism levels in fossil species provide otherwise unavailable insights into their adaptive strategies.Here, we apply a recently developed method of estimating sexual size dimorphism from fossil assemblages of unknown sex compositions, the posterior density peak (pdPeak) method (62), and reexamine canine sexual dimorphism in Ardipithecus ramidus at ∼4.5 Ma. We include newly available fossils recovered from the Middle Awash and Gona paleoanthropological research areas in the Afar Rift, Ethiopia (26, 63, 64) in order to obtain the most reliable dimorphism estimates currently possible. We apply the same method to Australopithecus, Homo, and selected fossil apes, and evaluate canine sexual dimorphism through evolutionary time.We operationally define canine sexual dimorphism as the ratio between male and female means of basal canine crown diameters (the m/f ratio). Because the canines of Ar. ramidus, Au. anamensis, and extant and fossil apes are variably asymmetric in crown shape, we examine the maximum basal dimension of the crown. This can be either the mesiodistal crown diameter or a maximum diameter taken from the distolingual to mesiobuccal crown base (7, 27, 65). In the chronologically later Au. afarensis and all other species of Australopithecus sensu lato and Homo, we examine the more widely available conventional metric of buccolingual breadth, which corresponds to or approximates the maximum basal crown diameter. In anthropoid primates, canine height is more informative than basal canine diameter as a functional indicator of aggression and/or related display (14, 41–44). We therefore also examine available unworn and minimally worn fossil canines with reliable crown heights.     

Comparison of immune responses to a killed bivalent whole cell oral cholera vaccine between endemic and less endemic settings

Studies on safety, immunogenicity and efficacy of the killed, bivalent whole cell oral cholera vaccine (Shanchol) have been conducted in historically endemic settings of Asia. Recent cholera vaccination campaigns in Haiti and Guinea have also demonstrated favourable immunogenicity and effectiveness in nonendemic outbreak settings. We performed a secondary analysis, comparing immune responses of Shanchol from two randomised controlled trials performed in an endemic and a less endemic area (Addis Ababa) during a nonoutbreak setting. While Shanchol may offer some degree of immediate protection in primed populations living in cholera endemic areas, as well as being highly immunogenic in less endemic settings, understanding the characteristics of immune responses in each of these areas is vital in determining ideal dosing strategies that offer the greatest public health impact to populations from areas with varying degrees of cholera endemicity.     

Influence of delaying treatment after symptoms develop from subarachnoid hemorrhage: a preliminary analysis

Patients experiencing subarachnoid hemorrhage (SAH) symptoms may delay seeking medical attention, not realizing the severity of these symptoms. The purposes of this study were to determine (a) the length of time between the development of SAH symptoms in patients and when treatment was initially sought and (b) whether the delay in hospital admission had an effect on patient outcomes. Inclusion criteria were age (18-75 years) and diagnosis of severe SAH. Consent was obtained on 90 eligible patients admitted to the neurovascular intensive care unit. Outcomes were assessed at 3 months using the Glasgow Outcome Scale (GOS) and Modified Rankin Scale (MRS). Initial time delay, calculated by subtracting the time of initial symptom development from the time of admission to the emergency department (ED), ranged from 0.08 to 103 hours. There was no relationship between the initial time delay and GOS or MRS scores. There was a significant difference between the time to initial ED admission to a trauma ED and to a community ED; patients were admitted within 2.7 hours to a trauma ED admission, compared to 7 hours for a community ED admission. There was a significant relationship between the Hunt and Hess Scale and GOS and between the Hunt and Hess and MRS. There was a significant relationship between the Fisher Grade and GOS and between the Fisher Grade and MRS. This study shows that patients may delay treatment for nearly 7 hours after initial symptoms develop. This suggests that laypersons are not aware of SAH symptoms, thereby delaying ED admission and care. The study also suggests that more severe symptoms upon admission to the ED were related to poorer outcomes. Initial clinical presentation is a useful predictor for SAH outcomes. This study supports the idea that the general public needs to be educated on the symptoms of SAH.