Advances in scarless foetal wound healing and prospects for scar reduction in adults.

Healing after mammalian skin injury involves the interaction between numerous cellular constituents and regulatory factors, which together form three overlapping phases: an inflammatory response, a proliferation phase and a remodelling phase. Any slight variation in these three stages can substantially alter the healing process and resultant production of scars. Of particular significance are the mechanisms responsible for the scar-free phenomenon observed in the foetus. Uncovering such mechanisms would offer great expectations in the treatment of scars and therefore represents an important area of investigation. In this review, we provide a comprehensive summary of studies on injury-induced skin regeneration within the foetus. The information contained in these studies provides an opportunity for new insights into the treatment of clinical scars based on the cellular and molecular processes involved.

Exosomes derived from umbilical cord mesenchymal stem cells reduce microglia-mediated neuroinflammation in perinatal brain injury.

BACKGROUND: Preterm newborns are at high risk of developing neurodevelopmental deficits caused by neuroinflammation leading to perinatal brain injury. Human Wharton's jelly mesenchymal stem cells (hWJ-MSC) derived from the umbilical cord have been suggested to reduce neuroinflammation, in part through the release of extracellular vesicle-like exosomes. Here, we studied whether exosomes derived from hWJ-MSC have anti-inflammatory effects on microglia-mediated neuroinflammation in perinatal brain injury. METHODS: Using ultracentrifugation, we isolated exosomes from hWJ-MSC culture supernatants. In an in vitro model of neuroinflammation, we stimulated immortalized BV-2 microglia and primary mixed glial cells with lipopolysaccharide (LPS) in the presence or absence of exosomes. In vivo, we introduced brain damage in 3-day-old rat pups and treated them intranasally with hWJ-MSC-derived exosomes. RESULTS: hWJ-MSC-derived exosomes dampened the LPS-induced expression of inflammation-related genes by BV-2 microglia and primary mixed glial cells. The secretion of pro-inflammatory cytokines by LPS-stimulated primary mixed glial was inhibited by exosomes as well. Exosomes interfered within the Toll-like receptor 4 signaling of BV-2 microglia, as they prevented the degradation of the NFκB inhibitor IκBα and the phosphorylation of molecules of the mitogen-activated protein kinase family in response to LPS stimulation. Finally, intranasally administered exosomes reached the brain and reduced microglia-mediated neuroinflammation in rats with perinatal brain injury. CONCLUSIONS: Our data suggest that the administration of hWJ-MSC-derived exosomes represents a promising therapy to prevent and treat perinatal brain injury.

Prenatal exposure to pyrrolizidine alkaloids induced hepatotoxicity and pulmonary injury in fetal rats.

Hepatic and pulmonary toxicity in fetal rats induced by pyrrolizidine alkaloids (PAs) was investigated. Retrorsine (RTS) or monocrotaline (MCT) was intragastrically administered during pregnancy. The reduction of body and tail lengths was consistent with body weight loss in PA-exposed fetuses, and pathological lesions in liver and lung were observed only in fetuses. Both PAs reduced fetal serum transaminase activities. The GSH/GSSG ratio, GSH peroxidase and superoxide dismutase activities also decreased but glutathione S-transferase activity increased in fetal lung, especially for MCT. The pyrrole-protein adducts in fetal liver and lung could be detected, and those adducts in RTS fetal lungs were about 65% of those in MCT group. In conclusion, prenatal PAs exposure induced fetal hepatic and pulmonary toxicities through the generation of pyrrole metabolites and oxidative injury. The difference on fetal pulmonary redox homeostasis between two PAs groups might be associated with the content of PAs migrated to fetal lungs.

High Prenatal Exposure to Bisphenol A Reduces Anogenital Distance in Healthy Male Newborns.

OBJECTIVE: To estimate the relationship between cord blood bisphenol A (BPA) levels and anogenital measurements in healthy newborns. METHODS: Pregnancy and birth history, together with body mass and length data, anogenital measurements, penile measurements and cord blood samples were obtained from healthy newborns. Cord blood concentration of BPA was analyzed by sandwich enzyme-linked immunosorbent assays kit. RESULTS: Among 130 healthy newborns (72 boys, 58 girls), mean anopenile distance was 45.2±6 mm and anoscrotal distance was 21.9±5.4 mm in boys; mean anoclitoral distance was 33.8±6.6 mm and mean anofourchette distance was 12.2±4.9 mm in girls. Mean cord blood BPA level was 4.75±2.18 ng/mL. 90th percentile value for cord blood BPA was 8.26 ng/mL and the analysis showed a statistically significant correlation between anoscrotal distance and cord blood BPA levels above the 90th percentile (p=0.047) in boys. The changes in anogenital distance in girls were not statistically significant. CONCLUSION: We showed a significant association between high cord blood BPA levels and shortened anoscrotal distance in male newborns. However, this result should be interpreted with caution since there were no significant external genital abnormalities in our study group.

Prenatal ischemia deteriorates white matter, brain organization, and function: implications for prematurity and cerebral palsy.

Cerebral palsy (CP) describes a group of neurodevelopmental disorders of posture and movement that are frequently associated with sensory, behavioral, and cognitive impairments. The clinical picture of CP has changed with improved neonatal care over the past few decades, resulting in higher survival rates of infants born very preterm. Children born preterm seem particularly vulnerable to perinatal hypoxia-ischemia insults at birth. Animal models of CP are crucial for elucidating underlying mechanisms and for development of strategies of neuroprotection and remediation. Most animal models of CP are based on hypoxia-ischemia around the time of birth. In this review, we focus on alterations of brain organization and functions, especially sensorimotor changes, induced by prenatal ischemia in rodents and rabbits, and relate these alterations to neurodevelopmental disorders found in preterm children. We also discuss recent literature that addresses the relationship between neural and myelin plasticity, as well as possible contributions of white matter injury to the emergence of brain dysfunctions induced by prenatal ischemia.

Morphological and inflammatory changes in the skin of autopsied fetuses according to the type of stress.

INTRODUCTION: The fetal skin acts on the development and activation of the immune response via immune-neuroendocrine communication coordinated by corticotropin-releasing hormone. OBJECTIVE: This study aimed to evaluate the morphological and inflammatory changes in the skin due to acute stress and chronic stress, associated with perinatal asphyxia, ascending infection and congenital malformation. METHODS: We measured dermal and epidermal thickness, the diameter of keratinocytes, and the percentage of collagen and elastic fibers. Immunohistochemistry was used to evaluate both Langerhans cell and mast cell density, and corticotropin-releasing hormone expression in the epidermis, sebaceous gland, sebaceous duct, sudoriparous gland and in the hair follicle. RESULTS: The epidermis was thinner in the cases with perinatal asphyxia, ascending infection and chronic stress. The diameter of keratinocytes was smaller in ascending infection and chronic stress. Mast cell density showed an indirect correlation with gestational age. Corticotropin-releasing hormone expression was significantly higher in ascending infection and chronic stress. CONCLUSIONS: Chronic stress is associated with immunological and morphological changes in the skin of fetuses with perinatal asphyxia and ascending infection. Thus, corticotropin-releasing hormone seems to play a vital role in the differentiation and activation of innate and adaptive immune cells of the skin of fetuses.

An Autopsy Case of a Pregnant Woman With Severe Placental and Fetal Damage From Domestic Violence.

We present an autopsy case of a pregnant woman who was a victim of domestic violence. The deceased showed injuries mainly to her head and abdomen. Postmortem examination revealed 1400 mL of abdominal hemorrhage, ablation of the perimetrium, placental avulsion, and intracranial hematoma. The cause of death was diagnosed as hemorrhagic shock. The uterus contained a fetus of 7 months' gestational age. Fetal autopsy revealed laceration of the lungs, laceration and avulsion of the liver, and 15 mL of hemoperitoneum. Both placental and fetal injuries suggested repeated severe attacks to the abdomen, such as those expected to result from kicking or hitting.

Intrauterine fetal decapitation after a high-speed car crash.

Motor vehicle collisions are an important cause of blunt abdominal trauma in pregnant woman. Among the possible outcomes of blunt abdominal trauma, placental abruption, direct fetal trauma, and rupture of the gravid uterus are described. An interesting case of complete fetal decapitation with uterine rupture due to a high-velocity motor vehicle collision is described. The external examination of the fetus showed a disconnection between the cervical vertebrae C3 and C4. The autopsy examination showed hematic infiltration of the epicranic soft tissues, an overlap of the parietal bones, and a subarachnoid hemorrhage in the posterior part of interparietal area. Histological analysis was carried out showing a lack of epithelium and hemorrhages in the subcutaneous tissue, a hematic infiltration between the muscular fibers of the neck and between the collagen and deep muscular fibers of the tracheal wall. Specimens collected from the placenta and from the uterus showed a hematic infiltration with hypotrophy of the placental villi, fibrosis of the mesenchymal villi with ischemic phenomena of the membrane. The convergence of circumstantial data, autopsy results, and histological data led us to conclude that the neck lesion was vital and the cause of death was attributed to the motor vehicle collision.

Regenerative healing, scar-free healing and scar formation across the species: current concepts and future perspectives.

All species have evolved mechanisms of repair to restore tissue function following injury. Skin scarring is an inevitable and permanent endpoint for many postnatal organisms except for non-amniote vertebrates such as amphibians, which are capable of tissue regeneration. Furthermore, mammalian foetuses through mid-gestation are capable of rapid wound repair in the absence of scar formation. Notably, excessive cutaneous scar formation, such as hypertrophic and keloid scars, is a species limited clinical entity as it occurs only in humans, although wounds on the distal limbs of horses are also prone to heal with fibroproliferative pathology known as equine exuberant granulation tissue. Currently, there are no reliable treatment options to eradicate or prevent scarring in humans and vertebrates. The limited number of vertebrate models for either hypertrophic or keloid scarring has been an impediment to mechanistic studies of these diseases and the development of therapies. In this viewpoint essay, we highlight the current concepts of regenerative, scar-free and scar-forming healing compared across a number of species and speculate on areas for future research. Furthermore, in-depth investigative research into the mechanisms of scarless repair may allow for the development of improved animal models and novel targets for scar prevention. As the ability to heal in both a scarless manner and propensity for healing with excessive scar formation is highly species dependent, understanding similarities and differences in healing across species as it relates to the regenerative process may hold the key to improve scarring and guide translational wound-healing studies.

Microglia toxicity in preterm brain injury.

Microglia are the resident phagocytic cells of the central nervous system. During brain development they are also imperative for apoptosis of excessive neurons, synaptic pruning, phagocytosis of debris and maintaining brain homeostasis. Brain damage results in a fast and dynamic microglia reaction, which can influence the extent and distribution of subsequent neuronal dysfunction. As a consequence, microglia responses can promote tissue protection and repair following brain injury, or become detrimental for the tissue integrity and functionality. In this review, we will describe microglia responses in the human developing brain in association with injury, with particular focus on the preterm infant. We also explore microglia responses and mechanisms of microglia toxicity in animal models of preterm white matter injury and in vitro primary microglia cell culture experiments.

Fault and blame, insults to the perinatal brain may be remote from time of birth.

There is a certainty in malpractice cases that neurodevelopmental deficits are caused by preventable events at birth when the onset, nature, and timing of the insult in the antenatal and natal period are unknown. The biggest problem is determining timing. Electronic fetal monitoring is given excessive importance in legal cases. Before assigning fault on events at birth, a better understanding of developmental neurobiology and limitations of the present clinical biomarkers is warranted. The issues of single versus repeated episodes, timing of antenatal insults, pros and cons of legal arguments, interaction of various etiologic and anatomic factors are discussed.

Head circumference and height abnormalities in autism revisited: the role of pre- and perinatal risk factors.

Pre/perinatal risk factors and body growth abnormalities have been studied frequently as early risk markers in autism spectrum disorder (ASD), yet their interrelatedness in ASD has received very little research attention. This is surprising, given that pre/perinatal risk factors can have a substantial impact on growth trajectories in the first years of life. We aimed to determine which pre/perinatal factors were more prevalent in ASD children and if these factors differentially influenced body growth in ASD and control children. A total of 96 ASD and 163 control children matched for gender participated. Data of growth of head size and body length during the first 13 months of life were collected. Data on pre/perinatal risk factors were retrospectively collected through standardized questionnaires. Results indicated that after matching for SES, prematurity/low birth weight and being first born were more prevalent in the ASD versus the control group. In addition, with increasing age children with ASD tended to have a proportionally smaller head circumference compared to their height. However, the effect of prematurity/low birth weight on head growth corrected for height was significantly different in ASD and control children: premature/low birth weight control children showed a disproportionate larger head circumference in relation to height during their first year of life, whereas this effect was absent in premature/low birth weight ASD children. This may suggest that the etiology of abnormal growth is potentially different in ASD and control children: where abnormal growth in control children is related to suboptimal conditions in the uterus, abnormal growth in ASD may be more strongly related to the causal factors that also increase the risk for ASD. However, prospective studies measuring growth and ASD characteristics in both premature/low birth weight and a terme children are necessary to support this conclusion.

Are peripapillary intrascleral hemorrhages pathognomonic for abusive head trauma?

The American Academy of Pediatrics' Committee on Child Abuse and Neglect, Section on Ophthalmology, acknowledges that searching for retinal hemorrhages (RHs) in infants only in cases of suspected of abuse creates selection bias. However, they also recommend that postmortem eye removal might not be indicated "in children who have clearly died from witnessed severe accidental head trauma or otherwise readily diagnosed systemic medical conditions." Although infrequently described in the child abuse literature, peripapillary intrascleral hemorrhages (bleeding in the sclera at the optic nerve insertion)--putatively from severe repetitive acceleration/deceleration forces with or without blunt head trauma--have been considered essentially pathognomonic for abusive head trauma (shaken baby syndrome). We present two neonates who sustained accidental, severe in utero head injuries and had associated extensive RHs and optic nerve sheath hemorrhages with peripapillary intrascleral hemorrhages detected at autopsy. Neither neonate had a documented clinical fundal examination in the intensive care unit.

[Effects of repeated short-term immobilization stress on plastisity of brain cortical division and cognition in adult rats with normal and disturbed embryogenesis].

The aim of the work was the analysis of the changes in a number of labile synaptopodin-positi- ve dendritic spines in parietal cortex and the CA1 field of the hippocampus, which characterize plasticity of intracellular interaction, and of the memorization after short-term repeated immobili- zation stress (daily for 5 minutes, 10 days), both in control rats and in rats subjected to prenatal hypoxia (E14, 7% of O2, 3 hours). There were observed deterioration of short-term and long-term memory, decrease in number labile spines in the CA1 field of the hippocampus (for 17.3 ± 10.4%; p ≤ 0.05) and their increase in a molecular layer of brain parietal cortex (for 36.9 ± 9.2%) at the adult rats with normal embryogenesis after immobilization stress in comparison with control intact animals. At the rats subjected to a prenatal hypoxia, regardless of that, they were ex- posed to an immobilized stress at an adult stage or not, was noted both violation of short-term and long-term memory, and decrease in number labile spines in the CA1 field of the hippocampus (for 22.9 ± 10.5%) and parietal cortex (for 28.1 ± 9.3%). The obtained data allow to conclude that the increase of plasticity providing adaptive behavior of animals, takes place in neocortical neuronal networks as a reply to a short-term repeating stress only at normal brain formation during embryo- genesis, while, violation of embryogenesis leads to decrease in plasticity and adaptive opportuni- ties of the nervous system during further ontogenesis.

In utero exposure to bisphenol-A and anogenital distance of male offspring.

BACKGROUND: Bisphenol-A (BPA) is an endocrine disruptor with widespread human exposure. The effect of in utero BPA exposure on human offspring remains largely unknown. METHODS: Anogenital distance (AGD) of sons of workers who did or did not have occupational BPA exposure during pregnancy were compared in an occupational cohort study. Parental BPA exposure level during the index pregnancy was estimated through a job-exposure matrix based on personal air sampling measurement. Maternal exposure was considered direct in utero exposure to the fetus, whereas paternal exposure was considered indirect in utero exposure. RESULTS: A total of 153 boys were included in the final analysis, among them 56 with parental occupational exposure during pregnancy and 97 without. After controlling for the boys' ages and weights using linear regression, parental occupational exposure to BPA during pregnancy was associated with shortened AGD in male offspring. The association was stronger for maternal exposure (p < 0.01). There was also a dose-response relationship with increased BPA exposure levels in pregnancy associated with greater magnitude of shortened AGD in male offspring, with a statistically significant trend for the association (p = 0.008). CONCLUSION: Our findings provide the first epidemiologic evidence that in utero BPA exposure may adversely affect male genital development.

Möbius sequence in a girl and arthrogryposis in her half-brother: distinct phenotypes caused by prenatal injuries.

Möbius sequence is a congenital facial and abducens nerve palsy, frequently associated to abnormalities of extremities. Arthrogryposis multiplex congenital is defined as a congenital fixation of multiple joints seldom of neurogenic origin. Both sequences must have a genetic origin, but usually are sporadic cases related to environmental factors such as drugs exposition and maternal trauma. A 5-year-old girl and a 1-year-old boy were born with Möbius sequence and arthrogryposis multiplex congenital, respectively. During pregnancies, the mother had vaginal bleeding at 7 weeks and used crack (free-based cocaine) in the first trimester, respectively. The girl also has equinovarus talipes and autistic behavior. The boy has arthrogryposis with flexion contractures of the feet and knees. A vascular disruption, due to hemorrhage and cocaine exposure, causing a transient ischemic insult to embryos in a critical period of development may be responsible for distinct phenotypes in these cases.

Anomalías físicas menores y esquizofrenia: revisión de la literatura / Minor physical anomalies and schizophrenia: literature review

La esquizofrenia es considerada una enfermedad del neurodesarrollo por muchos autores. Saber si en los pacientes hay variantes morfológicas producidas durante el desarrollo de áreas anatómicas diferentes al cerebro y entenderla relación de esas variantes con el desarrollo cerebral o con la exposición prenatal a posibles noxas, podría dar pistas sobre los eventos que llevan al trastorno. Variantes morfológicas inespecíficas producidas durante el primer y segundo trimestre de gestación denominadas anomalías físicas menores (AFM) que pueden ser usadas como marcadores de riesgo de una enfermedad en personas susceptibles se vienen relacionando con la esquizofrenia, independientemente de la región anatómica en la que se presenten. La importancia de estas anomalías en relación con la esquizofrenia estaría dada porque podrían ser el reflejo de un sustrato (esquizotaxia) heredado o adquirido como consecuencia de alguna injuria(s) que resultaría en la enfermedad en personas susceptibles. Esta idea se apoya además en evidencia indirecta proporcionada por estudios con familias, entre otros. Por otro lado, el rol de las AFM en otros trastornos del neurodesarrollo es similar al propuesto en la esquizofrenia (AU)

Schizophrenia is considered for many authors as a disease of neurodevelopment. Know if there are morphological variants in the patients produced during development of anatomical areas others than the brain and understand the relation of those variants with the brain development or with prenatal exposition to possible noxas could give clues about the events conducting to the disorder. Morphological unspecific variants generated during the first and second gestation trimester denominated minor physical anomalies (MPA) that can be used as risk markers of a disease in susceptible persons have been related with schizophrenia independently of the anatomical region they are. The importance of these anomalies in relation with schizophrenia is that they might be the reflex of a substratum (schizotaxia) inherited or acquired as a consequence of some injuries(s) that become into the disease in susceptible persons. Moreover this idea is supported in indirect evidence provided by studies with families, between others. In the other hand the role of the MPA in other disorders of neurodevelopment is similar to the one proposed in schizophrenia (AU)

Nicotinamide prevents the long-term effects of perinatal asphyxia on apoptosis, non-spatial working memory and anxiety in rats.

There is no established treatment for the long-term effects produced by perinatal asphyxia. Thus, we investigated the neuroprotection provided by nicotinamide against the effects elicited by perinatal asphyxia on hippocampus and behaviour observed at 30-90 days of age. Asphyxia was induced by immersing foetuses-containing uterine horns, removed from ready-to-deliver rats into a water bath at 37 degrees C for 20 min. Caesarean-delivered siblings were used as controls. Saline or nicotinamide (0.8 mmol/kg, i.p.) was administered to control and asphyxia-exposed animals 24, 48, and 72 h after birth. The animals were examined for morphological changes in hippocampus, focusing on delayed cell death and mossy fibre sprouting, and behaviour, focusing on cognitive behaviour and anxiety. At the age of 30-45 days, asphyxia-exposed rats displayed (1) increased apoptosis, assessed in whole hippocampus by nuclear Hoechst staining, and (2) increased mossy fibre sprouting, restricted to the stratum oriens of dorsal hippocampus, assessed by Timm's staining. Rats from the same cohorts displayed (3) deficits in non-spatial working memory, assessed by a novel object recognition task, and (4) increased anxiety, assessed by an elevated plus-maze test when examined at the age of 90 days. Nicotinamide prevented the effects elicited by perinatal asphyxia on apoptosis, working memory, and anxiety.

Experimental analysis of the relationship between simulated low-velocity rear-end collisions and fetal outcomes of pregnant rats.

Our study aimed to define the risk for a human fetus of rear-end vehicle collisions. We therefore performed drop tests using pregnant SLC Wistar rats. Pressure applied to the rat uterus and rectum at various stages of acceleration was measured. After being dropped, rats were observed throughout pregnancy. At birth, the numbers, weight and the occurrence of physical anomalies among pups were followed-up for 28 days. Uterine pressure increased exponentially from 2.1 +/- 0.3 kPa at 19-fold gravity (G) to 13.9 +/- 0.8 kPa at 92-fold G. These values are much lower than the mechanical failure level of human fetal membrane tissue or of those at risk of adverse fetal outcomes. Neither the average number of offspring per pregnant rat nor the average body weight of newborn pups differed significantly between control pregnant rats and those which had been exposed to acceleration of 46-fold or 92-fold G. Other variables such as maternal mental distress, motion effects of amniotic fluid or seatbelt-induced uterine injuries might contribute to fetal loss.