Trepanations in non-adults of the 16th to 18th C. The osteological series of the Church of the Assumption of Valdepeñas (Ciudad Real, Spain).

OBJECTIVE: To investigate the presence of trepanations in an early Modern Age, skeletal collection documented in medical treatises but infrequently reported in osteological collections. MATERIALS: Analyses were conducted on 387 non-adult crania from the ossuary in the church of the Assumption of Valdepeñas (16th - 18th C.), Ciudad Real, Spain. METHODS: All complete or semi-complete crania of non-adults (aged 3-20 years) were macroscopically examined. RESULTS: Trepanation was detected in two adolescents aged 14 and 20 years; no evidence of their survival was observed. CONCLUSIONS: These findings suggest that trepanation was carried out in rural areas as Valdepeñas in the 16th-18th centuries, where the selection of instruments indicates knowledge of contemporaneous medical treatises. SIGNIFICANCE: The present study provides new data on trepanation and how it was performed in adolescents during this period. LIMITATIONS: Understanding the motive for these interventions is highly challenging in the absence of bone lesions, and their occurrence is likely underestimated due to the scant research in skeletal remains from the early Modern Age. SUGGESTIONS FOR FUTURE RESEARCH: Further palaeopathological analyses of osteological collections from this period will provide more information about how this surgical technique was perfected.

The neurobiology of insulin-like growth factor I: From neuroprotection to modulation of brain states.

After decades of research in the neurobiology of IGF-I, its role as a prototypical neurotrophic factor is undisputed. However, many of its actions in the adult brain indicate that this growth factor is not only involved in brain development or in the response to injury. Following a three-layer assessment of its role in the central nervous system, we consider that at the cellular level, IGF-I is indeed a bona fide neurotrophic factor, modulating along ontogeny the generation and function of all the major types of brain cells, contributing to sculpt brain architecture and adaptive responses to damage. At the circuit level, IGF-I modulates neuronal excitability and synaptic plasticity at multiple sites, whereas at the system level, IGF-I intervenes in energy allocation, proteostasis, circadian cycles, mood, and cognition. Local and peripheral sources of brain IGF-I input contribute to a spatially restricted, compartmentalized, and timed modulation of brain activity. To better define these variety of actions, we consider IGF-I a modulator of brain states. This definition aims to reconcile all aspects of IGF-I neurobiology, and may provide a new conceptual framework in the design of future research on the actions of this multitasking neuromodulator in the brain.

Sex estimation of the humerus: A geometric morphometric analysis in an adult sample.

Sex estimation is the keystone for positive identification when an unidentified human body is recovered in forensic contexts. However, in complex death scenes such as mass disasters, the remains are often fleshed, mutilated, burned, and/or commingled. In situations such as these where it is not possible to analyze pelvis and/or cranium data, traditional metric and qualitative morphological methods on postcranial bones can yield unsatisfactory results. In such cases, geometric morphometric techniques offer an alternative to the analysis of both shape and size components of morphological variation that can be of great utility for sex estimation in forensic investigations. The study population consisted of 72 well-preserved adult humeri (40 males and 32 females; mean age of 62 years) that were photographed in standardized positions with landmarks located in four two-dimensional views of the humerus (anterior surface of the proximal epiphysis, and anterior, posterior and inferior surface of distal epiphysis). Principal components analysis, canonical variates analysis and discriminant analysis were applied. The data indicated that males and females were classified with low levels of accuracy (54.95-77.92% for males; 56.87-71.78% for females) based on shape variables. However, when the shape variable was combined with the centroid size, the levels of accuracy increased (81.86-94.92% for males; 84.08-94.88% for females). To obtain larger differences between males and females, it is necessary the combination of centroid size with shape variables; the shape of the humerus is insufficient to discriminate sex with accuracy.

Reliability, reproducibility and validity of the conventional buccolingual and mesiodistal measurements on 3D dental digital models obtained from intra-oral 3D scanner.

OBJECTIVE: The aims of this study were to assess the reliability, reproducibility and validity of mesiodistal and buccolingual measurements comparing these measurements collected using an electronic hand-held digital calliper, on dry dentitions and on dental casts, with measurements obtained from 3D digital models created using a portable intra-oral scanner. DESIGN: The mesiodistal and buccolingual diameter of the crown of 1304 teeth were measured on dry dentitions and on dental casts, and secondly on 3D digital models created using an intra-oral 3D scanner. Reliability, reproducibility and validity were evaluated using the intraclass correlation coefficient (ICC) and the Bland-Altman graphic method. RESULTS: The results of the intraclass correlation coefficient expressed an excellent degree of agreement in the intra- and inter-observer error analysis, as well as in the comparison of the mesiodistal and buccolingual dimensions taken with the calliper and those taken in digital 3D models. The results of the Bland-Altman method showed that the greatest differences were found in the mesiodistal diameter of the molars and in the buccolingual diameter of the upper premolars. CONCLUSIONS: Mesiodistal and buccolingual measurements obtained from digital 3D models are suitable for recording dentitions for forensic purposes.

Cell-specific expression of insulin/insulin-like growth factor-I receptor hybrids in the mouse brain.

Insulin (IR) and insulin-like growth factor I (IGF-IR) receptors share structural homology and can form hybrid heterodimers. While different observations suggest that hybrid receptors are important in physiology and pathology, little is known about their function in the brain. To gain further insight into the role of IR/IGF-IR hybrids in this organ, we analyzed their cellular distribution in the mouse brain. We combined proximity ligation assays (PLA) for IR and IGF-IR, a technique that detects close protein-protein interactions, with immunocytochemistry for brain cell markers to identify IR/IGF-IR hybrids in the major types of brain cells. Intriguingly, while all the types of brain cells analyzed co-express both receptors, only neurons, astroglia, and microglia show readily detectable IR/IGF-IR hybrids. Hybrid PLA signal was negligible in brain endothelial cells and was absent in oligodendrocytes. Hybrids were comparatively more abundant in neurons and peaked after brain development was completed. Cell-specific expression and greater abundance in the adult brain suggests specialized actions of IR/IGF-IR hybrids in this organ, particularly in neurons.

Insulin Peptides as Mediators of the Impact of Life Style in Alzheimer's disease.

The search for the cause of Alzheimer's disease (AD), that affects millions of people worldwide, is currently one of the most important scientific endeavors from a clinical perspective. There are so many mechanisms proposed, and so disparate changes observed, that it is becoming a challenging task to provide a comprehensive view of possible pathogenic processes in AD. Tauopathy (intracellular neurofibrillary tangles) and amyloidosis (extracellular amyloid plaques) are the anatomical hallmarks of the disease, and the formation of these proteinaceous aggregates in specific brain areas is widely held as the ultimate pathogenic mechanism. However, the triggers of this dysproteostasis process remain unknown. Further, neurofibrillary tangles and plaques may only constitute the last stages of a process of still uncertain origin. Thus, without an established knowledge of its etiology, and no cure in the horizon, prevention - or merely delaying its development, has become a last-resort goal in AD research. As with other success stories in preventive medicine, epidemiological studies have provided basic knowledge of risk factors in AD that may contribute to understand its etiology. Disregarding old age, gender, and ApoE4 genotype as non preventable risk factors, there are diverse life-style traits - many of them closely related to cardiovascular health, that have been associated to AD risk. Most prominent among them are diet, physical and mental activity, exposure to stress, and sleep/wake patterns. We argue that all these life-style factors engage insulinergic pathways that affect brain function, providing a potentially unifying thread for life-style and AD risk. Although further studies are needed to firmly establish a link between faulty insulinergic function and AD, we herein summarize the evidence that this link should be thoroughly considered.

Circulating insulin-like growth factor I modulates mood and is a biomarker of vulnerability to stress: from mouse to man.

Individual susceptibility to anxiety disorders after maladaptive responses to stress is not well understood. We now report that while exploring stress responses in mice after traumatic brain injury (TBI), a condition associated to stress susceptibility, we observed that the anxiogenic effects of either TBI or exposure to life-threatening experiences (predator) were blocked when both stressors were combined. Because TBI increases the entrance into the brain of serum insulin-like growth factor I (IGF-I), a known modulator of anxiety with a wide range of concentrations in the human population, we then determined whether circulating IGF-I is related to anxiety measures. In mice, anxiety-like responses to predator were inversely related to circulating IGF-I levels. Other indicators of mood regulation such as sensitivity to dexamethasone suppression and expression levels of blood and brain FK506 binding protein 5 (FKBP5), a co-chaperone of the glucocorticoid receptor that regulates its activity, were also associated to circulating IGF-I. Indeed, brain FKBP5 expression in mice was stimulated by IGF-I. In addition, we observed in a large human cohort (n = 2686) a significant relationship between plasma IGF-I and exposure to recent stressful life events, while FKBP5 expression in blood cells was significantly associated to plasma IGF-I levels. Collectively, these data indicate that circulating IGF-I appears to be involved in mood homeostasis across different species. Furthermore, the data in mice allow us to indicate that IGF-I may be acting at least in part by modulating FKBP5 expression.

A Coordinated Action of Blood-Borne and Brain Insulin-Like Growth Factor I in the Response to Traumatic Brain Injury.

In response to injury, the brain produces different neuroprotective molecules, such as insulin-like growth factor I (IGF-I). However, IGF-I is also taken up by the brain from the circulation in response to physiological stimuli. Herein, we analyzed in mice the relative contribution of circulating and locally produced IGF-I to increased brain IGF-I levels after insult. Traumatic brain injury (TBI) induced by a controlled impact resulted in increased IGF-I levels in the vicinity of the lesion, but mice with low serum IGF-I showed significantly lower increases. Indeed, in normal mice, peripheral IGF-I accumulated at the lesion site after injury, and at the same time serum IGF-I levels decreased. Collectively, these data suggest that serum IGF-I enter into the brain after TBI and contributes to increased brain IGF-I levels at the injury site. This connection between central and circulating IGF-I provides an amenable route for treatment, as subcutaneous administration of IGF-I to TBI mice led to functional recovery. These latter results add further support to the use of systemic IGF-I or its mimetics for treatment of brain injuries.

A role for astrocytes in cerebellar deficits in frataxin deficiency: Protection by insulin-like growth factor I.

Inherited neurodegenerative diseases such as Friedreich's ataxia (FRDA), produced by deficiency of the mitochondrial chaperone frataxin (Fxn), shows specific neurological deficits involving different subset of neurons even though deficiency of Fxn is ubiquitous. Because astrocytes are involved in neurodegeneration, we analyzed whether they are also affected by frataxin deficiency and contribute to the disease. We also tested whether insulin-like growth factor I (IGF-I), that has proven effective in increasing frataxin levels both in neurons and in astrocytes, also exerts in vivo protective actions. Using the GFAP promoter expressed by multipotential stem cells during development and mostly by astrocytes in the adult, we ablated Fxn in a time-dependent manner in mice (FGKO mice) and found severe ataxia and early death when Fxn was eliminated during development, but not when deleted in the adult. Analysis of underlying mechanisms revealed that Fxn deficiency elicited growth and survival impairments in developing cerebellar astrocytes, whereas forebrain astrocytes grew normally. A similar time-dependent effect of frataxin deficiency in astrocytes was observed in a fly model. In addition, treatment of FGKO mice with IGF-I improved their motor performance, reduced cerebellar atrophy, and increased survival. These observations indicate that a greater vulnerability of developing cerebellar astrocytes to Fxn deficiency may contribute to cerebellar deficits in this inherited disease. Our data also confirm a therapeutic benefit of IGF-I in early FRDA deficiency.

Circulating Insulin-Like Growth Factor I Regulates Its Receptor in the Brain of Male Mice.

The role of IGF-1 and its receptor (IGF-1R) in brain pathology is still unclear. Thus, either reduction of IGF-IR or treatment with IGF-1, two apparently opposite actions, has proven beneficial in brain diseases such as Alzheimer's dementia. A possible explanation of this discrepancy is that IGF-1 down-regulates brain IGF-1R levels, as previously seen in a mouse Alzheimer's dementia model. We now explored whether under normal conditions IGF-1 modulates its receptor. We first observed that in vitro, IGF-1 reduced IGF-1R mRNA levels in all types of brain cells including neurons, astrocytes, microglia, endothelial cells, and oligodendrocytes. IGF-1 also inhibited its own expression in neurons and brain endothelium. Next, we analyzed the in vivo actions of IGF-1. Because serum IGF-1 can enter the brain, we injected mice with IGF-1 ip. As soon as 1 hour after the injection, decreased hippocampal IGF-1 levels were observed, followed by increased IGF-1 and IGF-1R mRNAs 6 hours later. Because environmental enrichment (EE) stimulates the entrance of serum IGF-1 into the brain, we analyzed whether a physiological entrance of IGF-1 also produced changes in brain IGF-1R. Stimulation of IGF-1R by EE triggered a gradual decrease in hippocampal IGF-1 levels. After 6 hours of EE exposure, IGF-1 levels reached a significant decrease in parallel with increased IGF-1R expression. After longer times, IGF-1R mRNA levels returned to baseline. Thus, under nonpathological conditions, IGF-1 regulates brain IGF-1R. Because baseline IGF-1R levels are rapidly restored, a tight control of brain IGF-1R expression seems to operate under physiological conditions.

Exercise and cerebrovascular plasticity.

Aging impairs cerebrovascular plasticity and subsequently leads cerebral hypoperfusion, which synergistically accelerates aging-associated cognitive dysfunction and neurodegenerative diseases associated with impaired neuronal plasticity. On the other hand, over two decades of researches have successfully demonstrated that exercise, or higher level of physical activity, is a powerful and nonpharmacological approach to improve brain function. Most of the studies have focused on the neuronal aspects and found that exercise triggers improvements in neuronal plasticity, such as neurogenesis; however, exercise can improve cerebrovascular plasticity as well. In this chapter, to understand these beneficial effects of exercise on the cerebral vasculature, we first discuss the issue of changes in cerebral blood flow and its regulation during acute bouts of exercise. Then, how regular exercise improves cerebrovascular plasticity will be discussed. In addition, to shed light on the importance of understanding interactions between the neuron and cerebral vasculature, we describe neuronal activity-driven uptake of circulating IGF-I into the brain.

Dispersion assessment in the location of facial landmarks on photographs.

The morphological assessment of facial features using photographs has played an important role in forensic anthropology. The analysis of anthropometric landmarks for determining facial dimensions and angles has been considered in diverse forensic areas. Hence, the quantification of the error associated to the location of facial landmarks seems to be necessary when photographs become a key element of the forensic procedure. In this work, we statistically evaluate the inter- and intra-observer dispersions related to the facial landmark identification on photographs. In the inter-observer experiment, a set of 18 facial landmarks was provided to 39 operators. They were requested to mark only those that they could precisely place on 10 photographs with different poses (frontal, oblique, and lateral views). The frequency of landmark location was studied together with their dispersion. Regarding the intra-observer evaluation, three participants identified 13 facial points on five photographs classified in the frontal and oblique views. Each landmark location was repeated five times at intervals of at least 24 h. The frequency results reveal that glabella, nasion, subnasale, labiale superius, and pogonion obtained the highest location frequency in the three image categories. On the contrary, the lowest rate corresponds to labiale inferius and menton. Meanwhile, zygia, gonia, and gnathion were significantly more difficult to locate than other facial landmarks. They produced a significant effect on the dispersion depending on the pose of the image where they were placed, regardless of the type of observer that positioned them. In particular, zygia and gonia presented a statistically greater variation in the three image poses, while the location of gnathion is less precise in oblique view photographs. Hence, our findings suggest that the latter landmarks tend to be highly variable when determining their exact position.

Computer vision and soft computing for automatic skull-face overlay in craniofacial superimposition.

Craniofacial superimposition can provide evidence to support that some human skeletal remains belong or not to a missing person. It involves the process of overlaying a skull with a number of ante mortem images of an individual and the analysis of their morphological correspondence. Within the craniofacial superimposition process, the skull-face overlay stage just focuses on achieving the best possible overlay of the skull and a single ante mortem image of the suspect. Although craniofacial superimposition has been in use for over a century, skull-face overlay is still applied by means of a trial-and-error approach without an automatic method. Practitioners finish the process once they consider that a good enough overlay has been attained. Hence, skull-face overlay is a very challenging, subjective, error prone, and time consuming part of the whole process. Though the numerical assessment of the method quality has not been achieved yet, computer vision and soft computing arise as powerful tools to automate it, dramatically reducing the time taken by the expert and obtaining an unbiased overlay result. In this manuscript, we justify and analyze the use of these techniques to properly model the skull-face overlay problem. We also present the automatic technical procedure we have developed using these computational methods and show the four overlays obtained in two craniofacial superimposition cases. This automatic procedure can be thus considered as a tool to aid forensic anthropologists to develop the skull-face overlay, automating and avoiding subjectivity of the most tedious task within craniofacial superimposition.

A phosphatase-independent gain-of-function mutation in PTEN triggers aberrant cell growth in astrocytes through an autocrine IGF-1 loop.

Loss-of-function mutations in the phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome10) contribute to aberrant cell growth in part through upregulation of the mitogenic IGF-1/PI3K/Akt pathway. In turn, this pathway exerts a homeostatic feedback over PTEN. Using mutagenesis analysis to explore a possible impact of this mutual control on astrocyte growth, we found that truncation of the C-terminal region of PTEN (Δ51) associates with a marked increase in NFκB activity, a transcription factor overactivated in astrocyte tumors. Whereas mutations of PTEN are considered to lead to a loss-of-function, PTENΔ51, a truncation that comprises a region frequently mutated in human gliomas, displayed a neomorphic (gain-of-function) activity that was independent of its phosphatase activity. This gain-of-function of PTENΔ51 includes stimulation of IGF-1 synthesis through protein kinase A activation of the IGF-1 promoter. Increased IGF-1 originates an autocrine loop that activates Akt and NFκB. Constitutive activation of NFκB in PTENΔ51-expressing astrocytes leads to aberrant cell growth; astrocytes expressing this mutant PTEN generate colonies in vitro and tumors in vivo. Mutations converting a tumor suppressor such as PTEN into a tumor promoter through a gain-of-function involving IGF-1 production may further our understanding of the role played by this growth factor in glioma growth and help us define druggable targets for personalized therapy.

Loss of serum IGF-I input to the brain as an early biomarker of disease onset in Alzheimer mice.

Circulating insulin-like growth factor I (IGF-I) enters the brain and promotes clearance of amyloid peptides known to accumulate in Alzheimer's disease (AD) brains. Both patients and mouse models of AD show decreased level of circulating IGF-I enter the brain as evidenced by a lower ratio of cerebrospinal fluid/plasma IGF-I. Importantly, in presymptomatic AD mice this reduction is already manifested as a decreased brain input of serum IGF-I in response to environmental enrichment. To explore a potential diagnostic use of this early loss of IGF-I input, we monitored electrocorticogram (ECG) responses to systemic IGF-I in mice. Whereas control mice showed enhanced ECG activity after IGF-I, presymptomatic AD mice showed blunted ECG responses. Because nonhuman primates showed identically enhanced electroencephalogram (EEG) activity in response to systemic IGF-I, loss of the EEG signature of serum IGF-I may be exploited as a disease biomarker in AD patients.

Early brain amyloidosis in APP/PS1 mice with serum insulin-like growth factor-I deficiency.

The influence of insulin-like growth factor I (IGF-I) on the progression of Alzheimer's disease (AD) is discussed controversially. To help clarify the role of this circulating neurotrophic factor in brain amyloidosis, the major pathological trait in AD, we analyzed plaque formation in a mouse model of AD transgenic for human APP and PS1 mutations with reduced serum IGF-I levels (LIDAD mice). We found that brain amyloidosis in LIDAD mice appeared earlier than in AD mice, at 2 months of age, while attained comparable levels at 6 months. In parallel, early microgliosis was observed in LIDAD mice also at 2 months and remained exacerbated at 6 months. Collectively, these observations suggest a role of serum IGF-I in delaying early brain amyloidosis.

Regulation of the phosphatase calcineurin by insulin-like growth factor I unveils a key role of astrocytes in Alzheimer's pathology.

Whether insulin-like growth factor I (IGF-I) signaling in Alzheimer's disease (AD) is beneficial or detrimental remains controversial. We now show that a competitive regulation by IGF-I of the phosphatase calcineurin in reactive, but not in quiescent astrocytes drives Alzheimer's pathology. Calcineurin de-phosphorylates the transcription factor Foxo3 in response to tumor necrosis factor-α (TNFα), an inflammatory cytokine increased in AD, activating nuclear factor-κB (NFκB) inflammatory signaling in astrocytes. In turn, IGF-I inactivates and displaces Foxo3 from calcineurin in TNFα-stimulated astrocytes by recruiting the transcription factor peroxisome proliferator-activated receptor-γ, and NFκB signaling is inhibited. This antagonistic mechanism reversibly drives the course of the disease in AD mice, even at advanced stages. As hallmarks of this calcineurin/Foxo3/NFκB pathway are present in human AD brains, treatment with IGF-I may be beneficial by antagonizing it.

Estimación de la estatura a través de la tibia en población contemporánea española adulta femenina / Estimation of stature from tibia length in female adult contemporary Spanish population

La estatura es un parámetro importante para el estudio e identificación de individuos a partir de restos óseos. Es una característica poblacional e individual, exclusiva de la especie humana, en la que intervienen factores diversos como la genética, el sexo o la alimentación. Dada la relación que existe entre la estatura de una persona y la longitud de sus huesos largos, en este estudio se propone un método de estimación de la estatura en base a la longitud de la tibia, en población española contemporánea femenina. La muestra de estudio está compuesta por las medidas de talla y tibia de 35 cadáveres de mujeres de acreditada procedencia peninsular, sin ningún factor de alteración de estos parámetros (fracturas, patologías que afecten al crecimiento, etc.). Se ha obtenido una fórmula que mejora la estimación que proporciona el método de Telkka, sobre todo en individuos de estatura menor o igual a 150 cm. No es necesario hacer correcciones de edad (AU)

The stature is an important parameter for the study and identification of individuals from skeletal remains. It is a population and individual characteristic, a parameter unique to the human species in the various factors involved such as genetics, sex, or feeding. Given the relationship between a person´s height and length of their long bones, this study proposes a method of estimation of stature based in the length of the tibia in female Spanish population. The sample consists of the measures of height and tibia of 35 female cadavers of Spanish origin acredited, without any alteration of these factors parameters (fractures, pathologies affecting growth, etc.). A formula that improves the estimation methods provided by Telkka, especially in individuals of height less or equal to 150 cm. It isn´t necessary to make corrections for age (AU)

IGF-I and the aging mammalian brain.

Insulin-like growth factors (IGFs) are important modulators of organismal life-span all along phylogeny. These growth factors are widely viewed as detrimental for long life by reducing tissue resistance to oxidative stress. However, IGF-I has been consistently shown to be a potent neuroprotective factor in mammals, and as such, a deterrent of brain aging. Conversely, recent data suggest that IGF-I may contribute to amyloid neurodegeneration underlying Alzheimer's disease. These opposing observations underline an incomplete understanding of the significance of this ancestral hormone pathway in relation to brain aging. It is possible that these opposite results are the consequence of using different experimental approaches. Thus, brain amyloid injury is reduced in mutant mice partially defective in IGF-I receptor function, whereas IGF-I is neuroprotective when administered to animal models of neurodegenerative disease or normal brain aging. This approach-dependent effect of IGF-I highlights a fundamental gap in our knowledge of the relationship between peripheral and brain IGF-I function and the actual biological impact of experimental modulation of brain IGF-I function. We suggest to directly address brain IGF-I function in the varying experimental approaches used to confirm that changes have taken place in the desired way.

Independent alterations in the central and peripheral somatosensory pathways in rat diabetic neuropathy.

Peripheral and central diabetic neuropathies were studied in streptozotocin-diabetic rats, using behavioral, biochemical and electrophysiological techniques. Diabetic rats showed thermal hypoalgesia and decreasing motor nerve conduction velocity at 4 and 8 weeks of diabetes. In addition, amplitude of the evoked potential recorded in primary somatosensory cortex after stimulation of the sciatic nerve was markedly reduced at 8 weeks of diabetes. This decrease was accompanied by decreases in GluR2/3 AMPA receptor subunits. These changes seem to be specific to the somatosensory system and to originate in higher centers since they were not present in the hippocampus and were not observed at the level of gracilis nucleus. Insulin-like growth factor I (IGF-I) treatment reversed the reduced thermal sensitivity and peripheral nerve conduction velocity but did not reverse changes in the CNS, suggesting that once initiated, both anomalies may develop independently in this model of diabetic neuropathy. In conclusion, the results indicate that diabetes induces a wide spectrum of alterations in the central somatosensory system that are independent of the decreases in peripheral sensory transmission that could be responsible for the disturbances in somatosensory perception observed in diabetes.