Cognition and freezing of gait in Parkinson's disease: A systematic review and meta-analysis.

Freezing of gait (FOG) is a common and disabling symptom in people with Parkinson's Disease (PwPD). Although cognition is thought to be worse in PwPD who freeze, a comprehensive analysis of this relationship will inform future research and clinical care. This systematic review and meta-analysis compared cognition between PwPD who do and do not exhibit FOG across a range of cognitive domains and assessed the impact of disease severity and medication status on this relationship. 145 papers (n = 9010 participants) were included in the analysis, with 144 and 138 articles meeting the criteria to assess moderating effects of disease severity and medication status, respectively. PwPD who freeze exhibited worse cognition than PwPD without FOG across global cognition, executive function/attention, language, memory, and visuospatial domains. Greater disease severity and "ON" levodopa medication status moderated the FOG status-cognition relationship in global cognitive performance but not in other cognitive domains. This meta-analysis confirmed that cognition is worse in PwPD with FOG and highlights the importance of disease severity and medication status in this relationship.

The relationship between plantar sensation and muscle onset during automatic postural responses in people with multiple sclerosis and healthy controls.

BACKGROUND: Plantar sensation is critical for balance control in people with multiple sclerosis (PwMS). While previous research has described its impact on standing balance, the influence of plantar sensation during automatic postural responses (APRs) is not well understood in PwMS. The purpose of this study was to characterize the relationship between plantar sensation and APRs in PwMS and controls. A secondary aim was to determine whether the relationship between plantar sensation and APRs is different across PwMS and control groups. METHODS: 122 PwMS and 48 age-matched controls underwent forward and backward support-surface perturbations from stance. The onset of the tibialis anterior (TA) and medial gastrocnemius (MG) were the primary reactive balance outcome measures for backward and forward losses of balance, respectively. Plantar sensation was measured as the vibration sensation threshold (VT). RESULTS: As expected, PwMS had significantly higher (i.e., worse) VT (p<0.001) and an increased MG and TA onset latency (TA: p<0.001, MG: p = 0.01) compared to the control group. A higher VT was related to increased MG (p<0.001) and TA latency (p<0.001) across all participants. However, no moderating effect of group (control or PwMS) was observed for the relationship between VT and muscle onset (MG: p = 0.14; TA: p = 0.34). CONCLUSION: PwMS demonstrated poorer plantar sensation and delayed muscle onset during APRs compared to controls. Plantar sensation was also related to muscle onset after perturbations in all participants. Although this relationship was not moderated by group, this may be related to the lack of dynamic range of VT scores in controls. These results indicate that plantar sensation may be related to reactive balance and provides insight into a potential contributing factor of delayed automatic postural responses in people with MS.

Meta-analysis of the influence of lifestyle changes for preoperative weight loss on surgical outcomes.

BACKGROUND: The aim was to investigate whether preoperative weight loss results in improved clinical outcomes in surgical patients with clinically significant obesity. METHODS: This was a systematic review and aggregate data meta-analysis of RCTs and cohort studies. PubMed, MEDLINE, Embase and CINAHL Plus databases were searched from inception to February 2018. Eligibility criteria were: studies assessing the effect of weight loss interventions (low-energy diets with or without an exercise component) on clinical outcomes in patients undergoing any surgical procedure. Data on 30-day or all-cause in-hospital mortality were extracted and synthesized in meta-analyses. Postoperative thromboembolic complications, duration of surgery, infection and duration of hospital stay were also assessed. RESULTS: A total of 6060 patients in four RCTs and 12 cohort studies, all from European and North American centres, were identified. Most were in the field of bariatric surgery and all had some methodological limitations. The pooled effect estimate suggested that preoperative weight loss programmes were effective, leading to significant weight reduction compared with controls: mean difference -7·42 (95 per cent c.i. -10·09 to -4·74) kg (P < 0·001). Preoperative weight loss interventions were not associated with a reduction in perioperative mortality (odds ratio 1·41, 95 per cent c.i. 0·24 to 8·40; I2 = 0 per cent, P = 0·66) but the event rate was low. The weight loss groups had shorter hospital stay (by 27 per cent). No differences were found for morbidity. CONCLUSION: This limited preoperative weight loss has advantages but may not alter the postoperative morbidity or mortality risk.

Statins impact primary embryonic mouse neural stem cell survival, cell death, and fate through distinct mechanisms.

Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthesis pathway (CBP), and are used for the prevention of cardiovascular disease. The anti-inflammatory effects of statins may also provide therapeutic benefits and have led to their use in clinical trials for preeclampsia, a pregnancy-associated inflammatory condition, despite their current classification as category X (i.e. contraindicated during pregnancy). In the developing neocortex, products of the CBP play essential roles in proliferation and differentiation of neural stem-progenitor cells (NSPCs). To understand how statins could impact the developing brain, we studied effects of pravastatin and simvastatin on primary embryonic NSPC survival, proliferation, global transcription, and cell fate in vitro. We found that statins dose dependently decrease NSPC expansion by promoting cell death and autophagy of NSPCs progressing through the G1 phase of the cell cycle. Genome-wide transcriptome analysis demonstrates an increase in expression of CBP genes following pravastatin treatment, through activation of the SREBP2 transcription factor. Co-treatment with farnesyl pyrophosphate (FPP), a CBP metabolite downstream of HMG-CoA reductase, reduces SREBP2 activation and pravastatin-induced PARP cleavage. Finally, pravastatin and simvastatin differentially alter NSPC cell fate and mRNA expression during differentiation, through a non-CBP dependent pathway.

The potential impacts of 21st century climatic and population changes on human exposure to the virus vector mosquito Aedes aegypti.

The mosquito Aedes (Ae). aegypti transmits the viruses that cause dengue and chikungunya, two globally-important vector-borne diseases. We investigate how choosing alternate emissions and/or socioeconomic pathways may modulate future human exposure to Ae. aegypti. Occurrence patterns for Ae. aegypti for 2061-2080 are mapped globally using empirically downscaled air temperature and precipitation projections from the Community Earth System Model, for the Representative Concentration Pathway (RCP) 4.5 and 8.5 scenarios. Population growth is quantified using gridded global population projections consistent with two Shared Socioeconomic Pathways (SSPs), SSP3 and SSP5. Change scenarios are compared to a 1950-2000 reference period. A global land area of 56.9 M km2 is climatically suitable for Ae. aegypti during the reference period, and is projected to increase by 8% (RCP4.5) to 13% (RCP8.5) by 2061-2080. The annual average number of people exposed globally to Ae. aegypti for the reference period is 3794 M, a value projected to statistically significantly increase by 298-460 M (8-12%) by 2061-2080 if only climate change is considered, and by 4805-5084 M (127-134%) for SSP3 and 2232-2483 M (59-65%) for SSP5 considering both climate and population change (lower and upper values of each range represent RCP4.5 and RCP8.5 respectively). Thus, taking the lower-emissions RCP4.5 pathway instead of RCP8.5 may mitigate future human exposure to Ae. aegypti globally, but the effect of population growth on exposure will likely be larger. Regionally, Australia, Europe and North America are projected to have the largest percentage increases in human exposure to Ae. aegypti considering only climate change.

Skill sets required for the management of military head, face and neck trauma: a multidisciplinary consensus statement.

INTRODUCTION: The evolution of medical practice is resulting in increasing subspecialisation, with head, face and neck (HFN) trauma in a civilian environment usually managed by a combination of surgical specialties working as a team. However, the full combination of HFN specialties commonly available in the NHS may not be available in future UK military-led operations, necessitating the identification of a group of skill sets that could be delivered by one or more deployed surgeons. METHOD: A systematic review was undertaken to identify those surgical procedures performed to treat acute military head, face, neck and eye trauma. A multidisciplinary consensus group was convened following this with military HFN trauma expertise to define those procedures commonly required to conduct deployed, in-theatre HFN surgical combat trauma management. RESULTS: Head, face, neck and eye damage control surgical procedures were identified as comprising surgical cricothyroidotomy, cervico-facial haemorrhage control and decompression of orbital haemorrhage through lateral canthotomy. Acute in-theatre surgical skills required within 24 hours consist of wound debridement, surgical tracheostomy, decompressive craniectomy, intracranial pressure monitor placement, temporary facial fracture stabilisation for airway management or haemorrhage control and primary globe repair. Delayed in-theatre procedures required within 5 days prior to predicted evacuation encompass facial fracture fixation, delayed lateral canthotomy, evisceration, enucleation and eyelid repair. CONCLUSIONS: The identification of those skill sets required for deployment is in keeping with the General Medical Council's current drive towards credentialing consultants, by which a consultant surgeon's capabilities in particular practice areas would be defined. Limited opportunities currently exist for trainees and consultants to gain experience in the management of traumatic head, face, neck and eye injuries seen in a kinetic combat environment. Predeployment training requires that the surgical techniques described in this paper are covered and should form the curriculum of future military-specific surgical fellowships. Relevant continued professional development will be necessary to maintain required clinical competency.

Antenatal dexamethasone exposure differentially affects distinct cortical neural progenitor cells and triggers long-term changes in murine cerebral architecture and behavior.

Antenatal administration of synthetic glucocorticoids (sGC) is the standard of care for women at risk for preterm labor before 34 gestational weeks. Despite their widespread use, the type of sGC used and their dose or the dosing regimens are not standardized in the United States of America or worldwide. Several studies have identified neural deficits and the increased risk for cognitive and psychiatric disease later in life for children administered sGC prenatally. However, the precise molecular and cellular targets of GC action in the developing brain remain largely undefined. In this study, we demonstrate that a single dose of glucocorticoid during mid-gestation in mice leads to enhanced proliferation in select cerebral cortical neural stem/progenitor cell populations. These alterations are mediated by dose-dependent changes in the expression of cell cycle inhibitors and in genes that promote cell cycle re-entry. This leads to changes in neuronal number and density in the cerebral cortex at birth, coupled to long-term alterations in neurite complexity in the prefrontal cortex and hippocampus in adolescents, and changes in anxiety and depressive-like behaviors in adults.

Optimising ballistic facial coverage from military fragmenting munitions: a consensus statement.

VIRTUS is the first United Kingdom (UK) military personal armour system to provide components that are capable of protecting the whole face from low velocity ballistic projectiles. Protection is modular, using a helmet worn with ballistic eyewear, a visor, and a mandibular guard. When all four components are worn together the face is completely covered, but the heat, discomfort, and weight may not be optimal in all types of combat. We organized a Delphi consensus group analysis with 29 military consultant surgeons from the UK, United States, Canada, Australia, and New Zealand to identify a potential hierarchy of functional facial units in order of importance that require protection. We identified the causes of those facial injuries that are hardest to reconstruct, and the most effective combinations of facial protection. Protection is required from both penetrating projectiles and burns. There was strong consensus that blunt injury to the facial skeleton was currently not a military priority. Functional units that should be prioritised are eyes and eyelids, followed consecutively by the nose, lips, and ears. Twenty-nine respondents felt that the visor was more important than the mandibular guard if only one piece was to be worn. Essential cover of the brain and eyes is achieved from all directions using a combination of helmet and visor. Nasal cover currently requires the mandibular guard unless the visor can be modified to cover it as well. Any such prototype would need extensive ergonomics and assessment of integration, as any changes would have to be acceptable to the people who wear them in the long term.

Venous malformations of the head and neck: current concepts in management.

Low-flow venous malformations are congenital lesions and they are the third most common vascular anomaly in the head and neck. In this paper, the third in a series of three educational reviews, we discuss current trends in their management, and include a summary of common sclerosant agents used in their control.

Research Resource: The Dexamethasone Transcriptome in Hypothalamic Embryonic Neural Stem Cells.

Exposure to excess glucocorticoids during fetal development has long-lasting physiological and behavioral consequences, although the mechanisms are poorly understood. The impact of prenatal glucocorticoids exposure on stress responses in juvenile and adult offspring implicates the developing hypothalamus as a target of adverse prenatal glucocorticoid action. Therefore, primary cultures of hypothalamic neural-progenitor/stem cells (NPSCs) derived from mouse embryos (embryonic day 14.5) were used to identify the glucocorticoid transcriptome in both males and females. NPSCs were treated with vehicle or the synthetic glucocorticoid dexamethasone (dex; 100nM) for 4 hours and total RNA analyzed using RNA-Sequencing. Bioinformatic analysis demonstrated that primary hypothalamic NPSC cultures expressed relatively high levels of a number of genes regulating stem cell proliferation and hypothalamic progenitor function. Interesting, although these cells express glucocorticoid receptors (GRs), only low levels of sex-steroid receptors are expressed, which suggested that sex-specific differentially regulated genes identified are mediated by genetic and not hormonal influences. We also identified known or novel GR-target coding and noncoding genes that are either regulated equivalently in male and female NPSCs or differential responsiveness in one sex. Using gene ontology analysis, the top functional network identified was cell proliferation and using bromodeoxyuridine (BrdU) incorporation observed a reduction in proliferation of hypothalamic NPSCs after dexamethasone treatment. Our studies provide the first characterization and description of glucocorticoid-regulated pathways in male and female embryonically derived hypothalamic NPSCs and identified GR-target genes during hypothalamic development. These findings may provide insight into potential mechanisms responsible for the long-term consequences of fetal glucocorticoid exposure in adulthood.

Noncoding RNAs that associate with YB-1 alter proliferation in prostate cancer cells.

The highly conserved, multifunctional YB-1 is a powerful breast cancer prognostic indicator. We report on a pervasive role for YB-1 in which it associates with thousands of nonpolyadenylated short RNAs (shyRNAs) that are further processed into small RNAs (smyRNAs). Many of these RNAs have previously been identified as functional noncoding RNAs (http://www.johnlab.org/YB1). We identified a novel, abundant, 3'-modified short RNA antisense to Dicer1 (Shad1) that colocalizes with YB-1 to P-bodies and stress granules. The expression of Shad1 was shown to correlate with that of YB-1 and whose inhibition leads to an increase in cell proliferation. Additionally, Shad1 influences the expression of additional prognostic markers of cancer progression such as DLX2 and IGFBP2. We propose that the examination of these noncoding RNAs could lead to better understanding of prostate cancer progression.

Genome-wide transcript profiling reveals novel breast cancer-associated intronic sense RNAs.

Non-coding RNAs (ncRNAs) play major roles in development and cancer progression. To identify novel ncRNAs that may identify key pathways in breast cancer development, we performed high-throughput transcript profiling of tumor and normal matched-pair tissue samples. Initial transcriptome profiling using high-density genome-wide tiling arrays revealed changes in over 200 novel candidate genomic regions that map to intronic regions. Sixteen genomic loci were identified that map to the long introns of five key protein-coding genes, CRIM1, EPAS1, ZEB2, RBMS1, and RFX2. Consistent with the known role of the tumor suppressor ZEB2 in the cancer-associated epithelial to mesenchymal transition (EMT), in situ hybridization reveals that the intronic regions deriving from ZEB2 as well as those from RFX2 and EPAS1 are down-regulated in cells of epithelial morphology, suggesting that these regions may be important for maintaining normal epithelial cell morphology. Paired-end deep sequencing analysis reveals a large number of distinct genomic clusters with no coding potential within the introns of these genes. These novel transcripts are only transcribed from the coding strand. A comprehensive search for breast cancer associated genes reveals enrichment for transcribed intronic regions from these loci, pointing to an underappreciated role of introns or mechanisms relating to their biology in EMT and breast cancer.

Minireview: the impact of antenatal therapeutic synthetic glucocorticoids on the developing fetal brain.

The life-threatening, emotional, and economic burdens of premature birth have been greatly alleviated by antenatal glucocorticoid (GC) treatment. Antenatal GCs accelerate tissue development reducing respiratory distress syndrome and intraventricular hemorrhage in premature infants. However, they can also alter developmental processes in the brain and trigger adverse behavioral and metabolic outcomes later in life. This review summarizes animal model and clinical studies that examined the impact of antenatal GCs on the developing brain. In addition, we describe studies that assess glucocorticoid receptor (GR) action in neural stem/progenitor cells (NSPCs) in vivo and in vitro. We highlight recent work from our group on two GR pathways that impact NSPC proliferation, ie, a nongenomic GR pathway that regulates gap junction intercellular communication between coupled NSPCs through site-specific phosphorylation of connexin 43 and a genomic pathway driven by differential promoter recruitment of a specific GR phosphoisoform.

The use of foam sclerotherapy to treat low-flow vascular malformations of the head and neck.

Liquid sclerotherapy, laser and surgery have been used in the treatment of head and neck vascular anomalies with variable success for many years. A multidisciplinary team consisting of plastic surgery, maxillofacial surgery and interventional radiology currently treats such lesions by converting liquid sclerosant into foam. Foam sclerotherapy is currently used successfully to treat varicosities of the lower limbs and in this study, we present four cases in which 3% sodium tetradecyl sulfate has been used to treat low-flow vascular malformations in the head and neck.

Caveolin-1 regulates genomic action of the glucocorticoid receptor in neural stem cells.

While glucocorticoids (GCs) are used clinically to treat many conditions, their neonatal and prenatal usage is increasingly controversial due to reports of delayed adverse outcomes, especially their effects on brain development. Such alterations may reflect the impact of GCs on neural progenitor/stem cell (NPSC) function. We previously demonstrated that the lipid raft protein caveolin-1 (Cav-1) was required for rapid GC signaling in embryonic mouse NPSCs operating through plasma membrane-bound glucocorticoid receptors (GRs). We show here that genomic GR signaling in NPSCs requires Cav-1. Loss of Cav-1 impacts the transcriptional response of many GR target genes (e.g., the serum- and glucocorticoid-regulated kinase 1 gene) that are likely to mediate the antiproliferative effects of GCs. Microarray analysis of wild-type C57 or Cav-1-deficient NPSCs identified approximately 100 genes that are differentially regulated by GC treatment. These changes in hormone responsiveness in Cav-1 knockout NPSCs are associated with the loss of GC-regulated phosphorylation of GR at serine 211 but not at serine 226. Chromatin recruitment of total GR to regulatory regions of target genes such as Fkbp-5, RhoJ, and Sgk-1, as well as p211-GR recruitment to Sgk-1, are compromised in Cav-1 knockout NPSCs. Cav-1 is therefore a multifunctional regulator of GR in NPSCs influencing both rapid and genomic action of the receptor to impact cell proliferation.

Differential subcellular localization of the glucocorticoid receptor in distinct neural stem and progenitor populations of the mouse telencephalon in vivo.

Glucocorticoids are given to pregnant women at risk for premature delivery to promote lung maturation. Despite reports of detrimental effects of glucocorticoids on telencephalic neural stem/progenitor cells (NSPCs), the regional and cellular expressions of the glucocorticoid receptor (GR) in various NSPC populations in the intact brain have not been thoroughly assessed. Therefore in this study we performed a detailed analysis of GR protein expression in the developing mouse ventral and dorsal telencephalon in vivo. At embryonic day 11.5 (E11.5), the majority of Pax6-positive radial glial cells (RGCs) and Tbr2-positive intermediate progenitor cells (IPCs) expressed nuclear GR, while a small number of RGCs on the apical ventricular zone (aVZ), expressed cytoplasmic GR. However, on E13.5, the latter population of RGCs increased in size, whereas abventricular NSPCs and especially neurons of the cortical plate, expressed nuclear GR. In IPCs, GR was always nuclear. A similar expression profile was observed throughout the ventral telencephalon, hippocampus and olfactory bulb, with NSPCs of the aVZ primarily expressing cytoplasmic GR, while abventricular NSPCs and mature cells primarily expressed nuclear GR. Close to birth, nuclear GR accumulated within specific cortical areas such as layer V, the subplate and CA1 area of the hippocampus. In summary, our data show that GR protein is present in early NSPCs of the dorsal and ventral telencephalon at E11.5 and primarily occupies the nucleus. Moreover, our study suggests that the subcellular localization of the receptor may be subjected to region and neurodevelopmental stage-specific regulation.

Serotypes and virulence profiles of atypical enteropathogenic Escherichia coli (EPEC) isolated from bovine farms and abattoirs.

AIMS: The objective of this study was to examine the prevalence of enteropathogenic Escherichia coli (EPEC) on beef and dairy farms and in beef abattoirs and to characterize the isolates in terms of serogroup and virulence markers. METHODS AND RESULTS: Bovine faecal samples (n = 1200), farm soil samples (n = 600), hide samples (n = 450) and carcass samples (n = 450) were collected from 20 farms and three abattoirs throughout Ireland over a 12-month period. After selective enrichment, samples testing positive for the intimin gene (eae) using PCR screening were cultured, and colonies were examined for the presence of the eae, vt(1) and vt(2) genes. Colonies that were positive for the intimin gene and negative for the verotoxin genes were further screened using PCR for a range of virulence factors including tir, espA, espB katP, espP, etpD, saa, sab, toxB, iha, lpfA(O157/OI-141) , lpfA(O113) and lpfA(O157/OI-154) . PCR screening was also used to screen for variations in the intimin gene (eae). Of the 2700 source samples analysed, 3.9% (47 of 1200) of faecal, 2% (12 of 600) of soil, 6.4% (29 of 450) of hide and 0.7% (3 of 450) of carcass samples were PCR positive (for the presence of the eae gene). All 140 isolates obtained were atypical EPEC (aEPEC), while θ and ß intimin types were common. The virulence factors hlyA, tir, lpfA (O113) , lpfA (O157/OI-154) , and iha were frequently detected, while lpfA(O157/OI-141) , saa, espA, espB and toxB were also present but to a lesser extent. CONCLUSIONS: It was concluded that cattle are a source of aEPEC, many of which have the virulence machinery necessary to be pathogenic to humans. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings suggest the need for increased research on aEPEC with particular emphasis on food safety and public health risk.