Locomotion speed determines gait variability in cerebellar ataxia and vestibular failure

Temporal gait variability is a critical parameter in patients with balance problems. Increased magnitude of temporal gait variability corresponds to a higher risk of falls. The purpose of this study was to investigate the influence of walking speed on temporal stride-to-stride variability in patients with cerebellar and vestibular deficits. A GAITRite system was used to analyze the gait of 40 patients with cerebellar ataxia, 22 patients with bilateral vestibular failure, and 51 healthy subjects over the entire range of the individual's speed capacity. The coefficient of variability of stride time was calculated for each walk. Temporal gait variability was increased in cerebellar patients and vestibular patients. The magnitude of this variability depended on walking speed in a disease-specific manner. In patients with cerebellar ataxia, variability was increased during slow (8.4 ± 5.3%, P < .01) and fast (7.9 ± 6.4%, P < .01) walking speed but was normal during preferred walking speed. This resulted in a speed-related U-shaped function of stride-time variability. Patients with vestibular failure had increased variability during slow walking (9.9 ± 4.3%, P < .01). During walking with medium and fast walking speed, stride time variability was normal. Minimal temporal gait variability appears to be attractive for the locomotor system in cerebellar patients because these patients preferred to walk at a velocity associated with minimal stride-time variability. In contrast to previous studies, vestibular patients accelerate rather than decelerate gait to achieve dynamic stability. This may be explained by reduced sensory integration during fast locomotion.     

Portal hypertension caused by acute cytomegalovirus infection with liver involvement in an immunocompetent patient

Primary infection by cytomegalovirus in immunocompetent patients is usually unapparent. We report a case of severe acute cytomegalovirus infection in a young immunocompetent male with pulmonary and hepatic involvement and portal hypertension who recovered without specific antiviral therapy with complete resolution of sonographic signs of portal hypertension after 6 months.     

Preimplantation Human Blastocyst‐Endometrial Interactions: The Role of Inflammatory Mediators

Immune factors such as cytokines, chemokines, and growth factors are known to play important roles in the preimplantation interactions and communication between the blastocyst and receptive endometrium. This crucial dialog occurs during the stages when the blastocyst is in the uterine cavity immediately preceding implantation and the establishment of pregnancy. Human preimplantation processes are difficult to study due to restrictions on tissue availability. This review focuses on the expression and role of immune factors in human blastocyst‐endometrial dialog during the very early stages of implantation. It highlights the importance of immune regulators and the need to develop new models to study human implantation.     

Cytokines and chemokines during human embryo implantation: roles in implantation and early placentation

The complex processes of embryo implantation and early placentation require a plethora of locally acting molecules, which are themselves tightly regulated. Among these are cytokines (including chemotactic chemokines), which are synthesized by several cell types at the maternal-fetal interface. Those produced by endometrial epithelium may be secreted apically into the uterine lumen, where they affect blastocyst development, migration, and attachment, or basally with effects on the transformation of the underlying stroma. Decidualized stromal cells, which subsequently form a major component of the decidua of pregnancy, also produce cytokines that act to drive the decidualization process and chemokines that are chemoattractants both for leukocytes such as uterine natural killer cells and macrophages, and for trophoblast migration. Activated leukocytes within the developing decidua also contribute regulatory cytokines to the local microenvironment. Disturbances in the production of individual cytokines have been demonstrated in the endometrium of some infertile women and in those with recurrent miscarriage. It is important to establish whether a signature of endometrial cytokines may provide a clinically useful indication of women who will experience difficulty in establishing a viable pregnancy.     

Interleukin 11 advances progesterone-induced decidualization of human endometrial stromal cells

Differentiation of endometrial stromal cells into decidual cells is crucial for embryo implantation and placentation. Interleukin (IL)-11 signalling is essential for adequate decidualization in the mouse uterus. We examined the role of IL-11 during progesterone-induced decidualization of human endometrial stromal cells over a 10-12 day period, using prolactin (PRL) production as a decidual marker. These cells produced biologically active IL-11 and expressed IL-11, IL-11Ralpha and PRL mRNA during decidualization. Neutralization of endogenous IL-11 with an anti-human (hu)IL-11 antibody (AB) reduced production of PRL from day 8 and insulin-like growth factor binding protein (IGFBP)-1, another marker of decidualization, from day 10 of culture. Following AB washout, PRL and IGFBP-1 secretion increased. Addition of recombinant (r)huIL-11 (10 or 100 ng/ml) to endometrial stromal cells increased secretion of PRL from day 4 and IGFBP-1 from day 6 compared with progesterone alone. Morphological signs of differentiation accompanied biochemical differentiation in the progesterone-treated cells and were further induced by exogenous rhuIL-11. Our observations demonstrate that human endometrial stromal cells produce biologically active IL-11, which promotes progesterone-induced decidualization. These results suggest that IL-11 has both paracrine and autocrine actions on human endometrial stromal cells and plays an important role in preparing the human endometrium for implantation.     

Dietary,lifestyle and clinicopathological factors associated with APC mutations and promoter methylation in colorectal cancers from the EPIC‐Norfolk study

The tumour suppressor APC is the most commonly altered gene in colorectal cancer (CRC). Genetic and epigenetic alterations of APC may therefore be associated with dietary and lifestyle risk factors for CRC. Analysis of APC mutations in the extended mutation cluster region (codons 1276‐1556) and APC promoter 1A methylation was performed on 185 archival CRC samples collected from participants of the European Prospective Investigation into Cancer (EPIC)‐Norfolk study, with the aim of relating these to high‐quality seven‐day dietary and lifestyle data collected prospectively. Truncating APC mutations (APC⁺) and promoter 1A methylation (PM⁺) were identified in 43% and 23% of CRCs analysed, respectively. Distal CRCs were more likely than proximal CRCs to be APC⁺ or PM⁺ (p = 0.04). APC⁺ CRCs were more likely to be moderately/well differentiated and microsatellite stable than APC^? CRCs (p = 0.05 and 0.03). APC⁺ CRC cases consumed more alcohol than their counterparts (p = 0.01) and PM⁺ CRC cases consumed lower levels of folate and fibre (p = 0.01 and 0.004). APC⁺ or PM⁺ CRC cases consumed higher levels of processed meat and iron from red meat and red meat products (p = 0.007 and 0.006). Specifically, CRC cases harbouring GC‐to‐AT transition mutations consumed higher levels of processed meat (35 versus 24 g/day, p = 0.04) and iron from red meat and red meat products (0.8 versus 0.6 mg/day, p = 0.05). In a logistic regression model adjusted for age, sex and cigarette‐smoking status, each 19 g/day (1SD) increment increase in processed meat consumption was associated with cases with GC‐to‐AT mutations (OR 1.68, 95% CI 1.03–2.75). In conclusion, APC⁺ and PM⁺ CRCs may be influenced by diet and GC‐to‐AT mutations in APC are associated with processed meat consumption, suggesting a mechanistic link with dietary alkylating agents, such as N‐nitroso compounds. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Swine dust induces cytokine secretion from human epithelial cells and alveolar macrophages

Exposure to swine dust causes airway inflammation with increased levels of proinflammatory cytokines, and inflammatory cells in nasal and bronchoalveolar lavage fluid (BALF) in healthy subjects. Earlier studies have suggested that lipopolysaccharides (LPS) might be an important proinflammatory factor in swine dust. Since respiratory epithelial cells and alveolar macrophages are target cells for the inhaled dust, we therefore compared the release of proinflammatory cytokines from normal human bronchial epithelial cells (NHBE), an epithelial cell line (A549) and from human alveolar macrophages obtained from BALF from healthy subjects in vitro after incubation with dust collected in swine houses or LPS. Swine dust or LPS was added to the wells with A549 cells or macrophages and incubated for 8 h at concentrations of 12.5, 25, 50 and 100 μg/ml. NHBE cells were incubated with swine dust at a concentration of 25, 50 or 100 μg/ml or with LPS at a concentration of 50 or 100 μg/ml and incubated for 24 h. The supernatants were collected, centrifuged, and IL-6, IL-1β and tumour necrosis factor-alpha (TNF-α) production was measured using an ELISA method and expressed per 10⁶ cells. Swine dust and LPS caused a dose-dependant increase of IL-6 production in NHBE cells, swine dust being more potent than LPS. In A549 cells, only swine dust, but not LPS caused an increase of IL-6 production. Neither swine dust nor LPS induced IL-1β or TNF-α release from A549 cells. Both swine dust and LPS caused a dose-dependent increase of IL-1β, IL-6 and TNF-α in alveolar macrophages. Swine dust which contained 2.2 (0.2) ng endotoxin/100 μg swine dust (0.02‰) was almost as potent as LPS in inducing cytokine release from alveolar macrophages in vitro. We conclude that both epithelial cells and alveolar macrophages have the capability to contribute to the release of proinflammatory cytokines following exposure to swine dust. Some agent(s) other than LPS in the dust contribute to the marked airway inflammatory reaction.