Puerperal Streptococcus pneumoniae endometritis : a case report and literature review

Streptococcus pneumoniae endometritis is an exceedingly rare clinical occurrence in the immunocompetent individual. This case report describes such an occurrence in an otherwise healthy woman 39 days post-normal vaginal delivery. The patient responded to prompt broad-spectrum intravenous antibiotics and made a full recovery. The clinical relevance of such a scenario, the likely pathogenesis of the event as well as a brief review of relevant clinical literature are discussed. Streptococcus pneumoniae genital infection was a well-documented clinical entity in the pre-antibiotic era with a high mortality rate – 26% for localised infection and 74% for peritonitis and sepsis. More recently, however, there have been only isolated reports of Streptococcus pneumoniae genital infection, with even less frequent accounts of this happening in immunocompetent individuals. In this report, we document a case of Streptococcus pneumoniae endometritis in a young, previously healthy female 39 days post-partum.peer-reviewe

Cannabidiol impairs neural tube closure in mouse whole embryo culture

BACKGROUND: Cannabidiol (CBD) is a nonpsychoactive constituent of cannabis widely available as a dietary supplement. Previous reports that it impairs the retinoid, sonic hedgehog, and folate metabolism pathways raise concern that it may impair closure of the embryonic neural tube (NT), producing NT defects including spina bifida and exencephaly. METHODS: We undertook teratogenicity testing of CBD in mouse whole embryo culture. RESULTS: At concentrations that do not diminish embryo viability, growth, or axial rotation, CBD dose-dependently impairs cranial NT closure, increasing the proportion of embryos that develop exencephaly. It concomitantly diminishes closure of the spinal NT, the posterior neuropore (PNP), producing longer neuropores at the end of culture which is a hallmark of spina bifida risk. Exposure to CBD does not disrupt the formation of long F-actin cables in surface ectoderm cells flanking the PNP or folding of the neuroepithelium at predictable hinge points. At the cellular level, CBD exposure does not alter proliferation or apoptosis of the spinal neuroepithelium. DISCUSSION: Thus, CBD acts selectively as a neuroteratogen predisposing to spina bifida and exencephaly in mouse whole embryo culture at exposure levels not associated with overt toxicity. Large-scale testing of CBD's effects on NT closure, particularly in at-risk groups, is warranted to inform its marketing to women of childbearing age

Sclerostin's role in bone's adaptive response to mechanical loading

Mechanical loading is the primary functional determinant of bone mass and architecture, and osteocytes play a key role in translating mechanical signals into (re)modelling responses. Although the precise mechanisms remain unclear, Wnt signalling pathway components, and the anti-osteogenic canonical Wnt inhibitor Sost/sclerostin in particular, play an important role in regulating bone's adaptive response to loading. Increases in loading-engendered strains down-regulate osteocyte sclerostin expression, whereas reduced strains, as in disuse, are associated with increased sclerostin production and bone loss. However, while sclerostin up-regulation appears to be necessary for the loss of bone with disuse, the role of sclerostin in the osteogenic response to loading is more complex. While mice unable to down-regulate sclerostin do not gain bone with loading, Sost knockout mice have an enhanced osteogenic response to loading. The molecular mechanisms by which osteocytes sense and transduce loading-related stimuli into changes in sclerostin expression remain unclear but include several, potentially interlinked, signalling cascades involving periostin/integrin, prostaglandin, estrogen receptor, calcium/NO and Igf signalling. Deciphering the mechanisms by which changes in the mechanical environment regulate sclerostin production may lead to the development of therapeutic strategies that can reverse the skeletal structural deterioration characteristic of disuse and age-related osteoporosis and enhance bones' functional adaptation to loading. By enhancing the osteogenic potential of the context in which individual therapies such as sclerostin antibodies act it may become possible to both prevent and reverse the age-related skeletal structural deterioration characteristic of osteoporosis

Age-Related Impairment of Bones' Adaptive Response to Loading in Mice is Associated with Sex-Related Deficiencies in Osteoblasts But No Change in Osteocytes

Bones adjust their mass and architecture to be sufficiently robust to withstand functional loading by adapting to their strain environment. This mechanism appears less effective with age, resulting in low bone mass. In male and female young adult (17-week-old) and old (19-month-old) mice, we investigated the effect of age in vivo on bones' adaptive response to loading and in vitro in primary cultures of osteoblast-like cells derived from bone cortices. Right tibias were axially loaded on alternate days for 2 weeks. Left tibias were non-loaded controls. In a separate group, the number of sclerostin-positive osteocytes and the number of periosteal osteoblasts were analyzed 24 hours after a single loading episode. The responses to strain of the primary osteoblast-like cells derived from these mice were assessed by EGR2 expression, change in cell number and Ki67 immunofluorescence. In young male and female mice, loading increased trabecular thickness and the number of trabecular connections. Increase in the number of trabecular connections was impaired with age but trabecular thickness was not. In old mice, the loading-related increase in periosteal apposition of the cortex was less than in young ones. Age was associated with a lesser loading-related increase in osteoblast number on the periosteal surface but had no effect on loading-related reduction in the number of sclerostin-positive osteocytes. In vitro, strain-related proliferation of osteoblast-like cells was lower in cells from old than young mice. Cells from aged female mice demonstrated normal entry into the cell cycle but subsequently arrested in G2 phase, reducing strain-related increases in cell number. Thus, in both male and female mice, loading-related adaptive responses are impaired with age. This impairment is different in females and males. The deficit appears to occur in osteoblasts' proliferative responses to strain rather than earlier strain-related responses in the osteocytes

The surface ectoderm exhibits spatially heterogenous tension that correlates with YAP localisation during spinal neural tube closure in mouse embryos

The single cell layer of surface ectoderm (SE) which overlies the closing neural tube (NT) plays a crucial biomechanical role during mammalian NT closure (NTC), challenging previous assumptions that it is only passive to the force-generating neuroepithelium (NE). Failure of NTC leads to congenital malformations known as NT defects (NTDs), including spina bifida (SB) and anencephaly in the spine and brain respectively. In several mouse NTD models, SB is caused by misexpression of SE-specific genes and is associated with disrupted SE mechanics, including loss of rostrocaudal cell elongation believed to be important for successful closure. In this study, we asked how SE mechanics affect NT morphology, and whether the characteristic rostrocaudal cell elongation at the progressing closure site is a response to tension anisotropy in the SE. We show that blocking SE-specific E-cadherin in ex utero mouse embryo culture influences NT morphology, as well as the F-actin cable. Cell border ablation shows that cell shape is not due to tension anisotropy, but that there are regional differences in SE tension. We also find that YAP nuclear translocation reflects regional tension heterogeneity, and that its expression is sensitive to pharmacological reduction of tension. In conclusion, our results confirm that the SE is a biomechanically important tissue for spinal NT morphogenesis and suggest a possible role of spatial regulation of cellular tension which could regulate downstream gene expression via mechanically-sensitive YAP activity

Disuse rescues the age-impaired adaptive response to external loading in mice

UNLABELLED: We aimed to determine whether aged bones diminished response to mechanical loading could be rescued by modulating habitual activity. By reducing background loading, aged bones response to loading increased to a level no different to young mice. This suggests, given the right stimulus, that ageing bone can respond to mechanical loading. INTRODUCTION: Age-related decline in bone mass has been suggested to represent an impaired ability of bone to adapt to its mechanical environment. In young mice, the tibias response to external mechanical loading has been shown to increase when habitual activity is reduced by sciatic neurectomy. Here we investigate if neurectomy can rescue bones response to loading in old mice. METHODS: The effect of tibial disuse, induced by unilateral sciatic neurectomy (SN), on the adaptive response to a single peak magnitude of dynamic load-engendered mechanical strain was assessed in 19-month-old (aged) mice. In a second experiment, a range of peak loads was used to assess the load magnitude-related effects of loading on a background of disuse in young adult and aged mice. Bone architecture was analysed using micro-computed tomography (μCT) and dynamic histomorphometry. RESULTS: In the first experiment, SN in aged mice was associated with a significant periosteal osteogenic response to loading not observed in sham-operated mice (7.98 ± 1.7 vs 1.02 ± 2.2 % increase in periosteally enclosed area, p < 0.05). In the second experiment, SN abrogated the expected age-related difference in the bones osteogenic response to peak strain magnitude (p > 0.05). CONCLUSIONS: These data suggest that bones age-related decline in osteogenic responsiveness to loading does not originate in bone cells to either assess, or appropriately respond to strain, but rather is likely to be due to inhibitory averaging effects derived from the habitual strains to which the bone is already adapted. If such strain averaging is applicable to humans, it suggests that gentle exercise may degrade the beneficially osteogenic effects of short periods of more vigorous activity

Exercise does not enhance aged bone's impaired response to artificial loading in C57Bl/6 mice

AbstractBones adapt their structure to their loading environment and so ensure that they become, and are maintained, sufficiently strong to withstand the loads to which they are habituated. The effectiveness of this process declines with age and bones become fragile fracturing with less force. This effect in humans also occurs in mice which experience age-related bone loss and reduced adaptation to loading. Exercise engenders many systemic and local muscular physiological responses as well as engendering local bone strain. To investigate whether these physiological responses influence bones' adaptive responses to mechanical strain we examined whether a period of treadmill exercise influenced the adaptive response to an associated period of artificial loading in young adult (17-week) and old (19-month) mice. After treadmill acclimatization, mice were exercised for 30min three times per week for two weeks. Three hours after each exercise period, right tibiae were subjected to 40cycles of non-invasive axial loading engendering peak strain of 2250με. In both young and aged mice exercise increased cross-sectional muscle area and serum sclerostin concentration. In young mice it also increased serum IGF1. Exercise did not affect bone's adaptation to loading in any measured parameter in young or aged bone. These data demonstrate that a level of exercise sufficient to cause systemic changes in serum, and adaptive changes in local musculature, has no effect on bone's response to loading 3h later. This study provides no support for the beneficial effects of exercise on bone in the elderly being mediated by systemic or local muscle-derived effects rather than local adaptation to altered mechanical strain

Old age and the associated impairment of bones’ adaptation to loading are associated with transcriptomic changes in cellular metabolism, cell-matrix interactions and the cell cycle

AbstractIn old animals, bone's ability to adapt its mass and architecture to functional load-bearing requirements is diminished, resulting in bone loss characteristic of osteoporosis. Here we investigate transcriptomic changes associated with this impaired adaptive response. Young adult (19-week-old) and aged (19-month-old) female mice were subjected to unilateral axial tibial loading and their cortical shells harvested for microarray analysis between 1h and 24h following loading (36 mice per age group, 6 mice per loading group at 6 time points). In non-loaded aged bones, down-regulated genes are enriched for MAPK, Wnt and cell cycle components, including E2F1. E2F1 is the transcription factor most closely associated with genes down-regulated by ageing and is down-regulated at the protein level in osteocytes. Genes up-regulated in aged bone are enriched for carbohydrate metabolism, TNFα and TGFβ superfamily components. Loading stimulates rapid and sustained transcriptional responses in both age groups. However, genes related to proliferation are predominantly up-regulated in the young and down-regulated in the aged following loading, whereas those implicated in bioenergetics are down-regulated in the young and up-regulated in the aged. Networks of inter-related transcription factors regulated by E2F1 are loading-responsive in both age groups. Loading regulates genes involved in similar signalling cascades in both age groups, but these responses are more sustained in the young than aged. From this we conclude that cells in aged bone retain the capability to sense and transduce loading-related stimuli, but their ability to translate acute responses into functionally relevant outcomes is diminished

National analyses on survival in Maltese adult patients on renal replacement therapy started during 2009–2012

Chronic kidney disease patients on maintenance dialysis (CKD 5D) experience major morbidity and mortality. No data on survival in Maltese dialysis patients exist; therefore, the aim of this study was to rigorously examine survival statistics in a complete cohort of Maltese CKD 5D patients. The study population was comprised of all incident chronic patients (N=328) starting dialysis at the renal unit, Mater Dei hospital, Msida, Malta, for 4 consecutive years (2009–2012). Each yearly cohort was analysed in detail up to 31st December 2017, providing up to 8 years follow-up. Demographics (male 65%; female 35%), aetiology of renal failure (diabetic kidney disease: n=191; 58.2%), comorbidities, transplant status, and death were documented. Data collection and follow up were completed and statistical analysis was performed on the aggregated cohorts with SPSS version 23 with censoring up to 31st December 2017. The cumulative adjusted 5-year overall survival in Maltese CKD 5D patients was 0.36 and 0.25 at 8 years. No statistical difference was observed according to the year of starting dialysis. Cox regression analysis showed that age and transplant status influenced survival. The unadjusted hazard of death increased by 3% for every 1-year increase in age and was increased by 7% if the patient did not receive a transplant, and overall 22% (n=72) of the entire cohort eventually received transplants. This study reports an approximate 65% mortality at 5 years in Maltese haemodialysis patients, a poor prognosis that, despite optimal medical management, is consistent with worldwide reports.peer-reviewe

How Personality Affects Vulnerability among Israelis and Palestinians Following the 2009 Gaza Conflict

Can the onset of PTSD symptoms and depression be predicted by personality factors and thought control strategies? A logical explanation for the different mental health outcomes of individuals exposed to trauma would seem to be personality factors and thought control strategies. Trauma exposure is necessary but not sufficient for the development of PTSD. To this end, we assess the role of personality traits and coping styles in PTSD vulnerability among Israeli and Palestinian students amid conflict.We also determine whether gender and exposure level to trauma impact the likelihood of the onset of PTSD symptoms. Five questionnaires assess previous trauma, PTSD symptoms, demographics, personality factors and thought control strategies, which are analyzed using path analysis. Findings show that the importance of personality factors and thought control strategies in predicting vulnerability increases in the face of political violence: the higher stress, the more important the roles of personality and thought control strategies. Thought control strategies associated with introverted and less emotionally stable personality-types correlate positively with higher levels of PTSD symptoms and depression, particularly among Palestinians. By extension, because mental health is key to reducing violence in the region, PTSD reduction in conflict zones warrants rethinking