Orthostatic tolerance is difficult to predict in recurrent syncope patients

Objectives  

We tested the hypothesis that detailed anthropometric and hemodynamic measurements predict orthostatic tolerance in neurally mediated syncope patients. In addition, we tested whether orthostatic tolerance is related to syncope frequency in real life.     

Macrophage migration inhibitory factor promotes cell death and aggravates neurologic deficits after experimental stroke

Multiple mechanisms contribute to tissue demise and functional recovery after stroke. We studied the involvement of macrophage migration inhibitory factor (MIF) in cell death and development of neurologic deficits after experimental stroke. Macrophage migration inhibitory factor is upregulated in the brain after cerebral ischemia, and disruption of the Mif gene in mice leads to a smaller infarct volume and better sensory-motor function after transient middle cerebral artery occlusion (tMCAo). In mice subjected to tMCAo, we found that MIF accumulates in neurons of the peri-infarct region, particularly in cortical parvalbumin-positive interneurons. Likewise, in cultured cortical neurons exposed to oxygen and glucose deprivation, MIF levels increase, and inhibition of MIF by (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) protects against cell death. Deletion of MIF in Mif^−/− mice does not affect interleukin-1β protein levels in the brain and serum after tMCAo. Furthermore, disruption of the Mif gene in mice does not affect CD68, but it is associated with higher galectin-3 immunoreactivity in the brain after tMCAo, suggesting that MIF affects the molecular/cellular composition of the macrophages/microglia response after experimental stroke. We conclude that MIF promotes neuronal death and aggravates neurologic deficits after experimental stroke, which implicates MIF in the pathogenesis of neuronal injury after stroke.     

Die Auswirkung definierter Varusdeformitäten am proximalen Humerus auf die Elevationskräfte des Armes

Objectives

This study investigated the hypothesis that different varus deformities of the humeral head decrease the efficiency of the M. supraspinatus (SSP) and increase the deltoid elevation forces.

Methods

A varus deformity model of the proximal humerus was developed with an intact rotator cuff and deltoid muscle in human specimens. Three groups were differentiated per random distribution: group I (n=8): 45° varus deformity, group II (n=8): 20° varus deformity, and a control group (n=8). The effect of different varus malunions (20° and 45° varus) on the SSP efficiency and on the arm elevation forces was analyzed with a robot-assisted shoulder simulator and a force-controlled hydraulic system in three defined phases of elevation: 0–30°, 30–60°, and 60–90°.

Results

The SSP efficiency (i.e., the degree of elevation per unit muscle force) was 0.12±0.03°/N in group I, 0.18±0.05°/N in group II, and 0.24±0.10°/N in the control group and was significantly lesser in group I than in group II (p=0.036) and in the control group (p=0.039). Under physiological loading of the rotator cuff, the deltoid elevation force per elevation angle was significantly greater in groups l and ll compared to the control group in the elevation phases between 0–30° and 60–90°. In case of an unloaded SSP (i.e., simulation of a SSP tear), the elevation forces were significantly greater in group l than in group ll (p=0.040), and in the control group (p=0.004) in the elevation phase between 60° and 90°.

Conclusion

Varus deformities of the humeral head significantly decreased the SSP efficiency (45° varus), and significantly increased the arm elevation forces (≥20° varus in the elevation phases 0–30° and 60–90°). The hypothesis of our study could be confirmed.     

Polyaxial Locked Implants in the Treatment of Type Vancouver B1 Periprosthetic Fractures of the Femur: Retrospective Clinical Examination in 58 Cases with Review of the Literature

We concluded a retrospective study of the outcomes of a consecutive series of Vancouver B1 and C femoral injuries using two specific locked implants. The study center is a dedicated trauma hospital with a large catchment area. Over a five-year period we treated 58 patients with a periprosthetic fracture of the femur with an angular stable plate, defined as the index procedure. The mean age at the index procedure was 72.4 years; 40 patients were female (69%). In 32 cases (55.2%) we saw a hip endoprosthesis, in 21 cases (36.2%) a knee endoprosthesis, and in five cases both (8.6%). Outcome measures were intra- and postoperative complications, bony union, degree of mobility and social status with comparison to the preoperative status, Barthel index, and timed ‘‘up and go’’ test. Union occurred in 56 cases (96.5%) after the index procedure. Three patients were bedridden before the injury; the remainder regained full weight-bearing status. The mean duration until full weight-bearing status in these patients was 8.6 weeks (4–13). Early implant failure with proximal dislocation of the screws occurred in two cases (3.5% revision rate). At follow up, 78% had maintained the same social status as before the injury. Fifty-two patients (89%) had regained their previous level of mobility. The mean Barthel index was 85 points (70–100) out of a possible 100, and improved from a mean of 35 points at the start of rehabilitation. It decreased on average by ten points compared to the preoperative status. The mean ‘‘up and go’’ time was measured as 21.4 s. In conclusion, polyaxial plates can achieve excellent surgical results. On the other hand, patients with this type of injury exhibit a clear deterioration in their social status, especially regarding lower limb motor function and self-independence.     

Risk factors for executive dysfunction after subthalamic nucleus stimulation in Parkinson's disease

A slight decline in cognitive functions and especially in executive functioning after deep brain stimulation (DBS) of the nucleus subthalamicus (STN) in patients with Parkinson's disease (PD) has been described. This study evaluated baseline parameters that contribute to a deterioration of cognitive functioning after DBS. We analyzed data from the neuropsychological protocol in a randomized controlled study comparing DBS with best medical treatment (BMT). Change scores were calculated for the cognitive domains “global cognitive functioning,” “memory,” “working memory,” “attention,” and “executive function.” These domain‐specific change scores were correlated with previously defined preoperative parameters. Compared with the BMT group (63 patients), the STN‐DBS group (60 patients) showed a significant decline only in the domain executive function 6 months after DBS, which was significantly correlated with age, levodopa‐equivalence dosage (LED) and axial subscore of the UPDRS in the off‐medication state at baseline. Multiple regression analysis showed that these three factors explained, however, only about 23% of the variance. Patients with higher age, higher baseline LED, and/or higher axial subscore of the UPDRS at baseline have an increased risk for worsening of executive function after STN‐DBS. High scores of these factors might reflect an advanced stage of disease progression. As these baseline factors explained the variance of the change score executive function only to a minor proportion, other factors including the surgical procedure, the exact placement of the electrode or postsurgical management might be more relevant for a decline in executive functioning after STN‐DBS. © 2010 Movement Disorder Society     

Effects of prolonged walking on neural and mechanical components of stretch responses in the human soleus muscle

After repeated passive stretching, tendinous tissue compliance increases in the human soleus (SOL) muscle–tendon unit. During movement, such changes would have important consequences for neural and mechanical stretch responses. This study examined the existence of such effects in response to a 75 min walking intervention. Eleven healthy subjects walked on a treadmill at 4 km h⁻¹ with a robotic stretch device attached to the left leg. Ultrasonography was used to measure SOL fascicle lengths, and surface EMG activity was recorded in the SOL and tibialis anterior (TA) muscles. Perturbations of 6 deg were imposed at three different measurement intervals: Pre (immediately before the walking intervention), Mid (after approximately 30 min of walking) and Post (immediately after the intervention). Between the Pre–Mid and Mid–Post intervals, subjects walked for 30 min at a gradient of 3%. After the intervention, the amplitude and velocity of fascicle stretch both decreased (by 46 and 59%, respectively; P < 0.001) in response to a constant external perturbation, as did short (33%; P < 0.01) and medium (25%; P < 0.01) latency stretch reflex amplitudes. A faster perturbation elicited at the end of the protocol resulted in a recovery of fascicle stretch velocities and short latency reflex amplitudes to the pre-exercise values. These findings suggest that repeated stretching and shortening of a muscle–tendon unit can induce short-term structural changes in the tendinous tissues during human walking. The data also highlight the effect of these changes on neural feedback from muscle sensory afferents.     

Endogenous LXA4 Circuits Are Determinants of Pathological Angiogenesis in Response to Chronic Injury

Inflammation and angiogenesis are intimately linked, and their dysregulation leads to pathological angiogenesis in human diseases. 15-lipoxygenase (15-LOX) and lipoxin A₄ receptors (ALX) constitute a LXA₄ circuit that is a key feature of inflammatory resolution. LXA₄ analogs have been shown to regulate vascular endothelial growth factor (VEGF)-A-induced angiogenic response in vitro. 15-LOX and ALX are highly expressed in the avascular and immune-privileged cornea. However, the role of this endogenous LXA₄ circuit in pathological neovascularization has not been determined. We report that suture-induced chronic injury in the cornea triggered polymorphonuclear leukocytes (PMN) infiltration, pathological neovascularization, and up-regulation of mediators of inflammatory angiogenesis, namely VEGF-A and the VEGF-3 receptor (FLT4). Up-regulation of the VEGF circuit and neovascularization correlated with selective changes in both 15-LOX (Alox15) and ALX (Fpr-rs2) expression and a temporally defined increase in basal 15-LOX activity. More importantly, genetic deletion of 15-LOX or 5-LOX, key and obligatory enzymes in the formation of LXA₄, respectively, led to exacerbated inflammatory neovascularization coincident with increased VEGF-A and FLT4 expression. Direct topical treatment with LXA₄, but not its metabolic precursor 15-hydroxyeicosatetraenoic acid, reduced expression of VEGF-A and FLT4 and inflammatory angiogenesis and rescued 15-LOX knockout mice from exacerbated angiogenesis. In summary, our findings and the prominent expression of 15-LOX and ALX in epithelial cells and macrophages place the LXA₄ circuit as an endogenous regulator of pathological angiogenesis.Formation of a new functional microvasculature, neovascularization, is a fundamental response to ischemia and a salient feature of wound healing. The primary function of newly formed blood vessels is to increase tissue oxygen tension and delivery of essential nutrients and effector cells to restore normal function. However, aberrant neovascularization is a hallmark feature of chronic inflammation and is associated with numerous pathological conditions that include diabetic retinopathy, Crohn''s Disease, atherosclerosis, and cancer.^1–3The growth of microvessels from existing vessels, angiogenesis, is tightly controlled by a range of angiogenic factors and inhibitors; a circuit that is highly evolved in avascular tissues such as the cornea. The vascular endothelial growth factor (VEGF) family of angiogenic factors and their receptors are key mediators of this process, which has led to the recent development and clinical use of anti-VEGF strategies for the treatment of pathological neovascularization in the retina, colon cancer, and lung cancer.^2–5 Many insights into the endogenous role of the VEGF network have been gained by using the cornea,^5,6 which maintains an immune-privileged and avascular state despite expression of VEGF-A and its immediate proximity to the vasculature.⁷ Specifically, recent findings have demonstrated that avascularity of the cornea requires expression of a soluble VEGF receptor-1 (sFLT1), which traps VEGF-A.⁸ In addition, the receptor for VEGF-C/VEGF-D, namely VEGF receptor-3 (VEGFR-3, FLT4), is a critical regulator of inflammatory neovascularization.^9–11 FLT4 is of special of interest because its essential expression during development becomes restricted primarily to lymph vessels and activation of this endothelial receptor is a critical step in initiating lymphangiogenesis. However, FLT4 expression is also up-regulated in microvessels of tumors and wounds, and in macrophages and in addition is constitutively expressed in corneal epithelial cells.^3,10–13 A recent report demonstrates that FLT4 is highly expressed in angiogenic sprouts and is a critical regulator of sustained heme-angiogenesis,¹² which underscores the potential key role of this receptor in pathological neovascularization.Inflammation is intimately associated with neovascularization especially during wound healing and ischemic injury. Lipid autacoids are some of the earliest signals that are released in response to injury or insult. In this regard, the 15-lipoxygenase pathway^14,15 is of interest as it is one of the most inducible genes in macrophages and highly expressed in mucosal and corneal epithelial cells. Macrophages and epithelial cells are important regulators of angiogenesis, especially in avascular tissue such as the cornea.^3,10,16 Macrophages have a central and well-documented role in angiogenesis, especially in tumors and inflammatory neovascularization. In the cornea, a well-established model tissue for studying inflammatory neovascularization, VEGF-A recruits macrophages, the major cell type to generate VEGF, which drives inflammatory heme and lymphangiogenesis. Corneal epithelial cells constitutively express the receptor for VEGF-C/VEGF-D (ie, FLT4), which has been proposed as a critical pathway for regulating inflammatory neovascularization.¹⁰Human 15-LOX (ALOX15 and ALOX15B) generate 15S-hydroxyeicosatetraenoic acid (HETE) and mouse 12/15-LOX (Alox15) generates 15S-HETE and 12S-HETE from arachidonic acid. 15-HETE and 12-HETE have been shown to induce proliferation, migration, and tube formation in endothelial cells.¹⁷ More importantly, 15-HETE is a key intermediate in the formation of the well-studied anti-inflammatory mediator lipoxin A₄ (LXA₄) that is generated via the rate-limiting enzyme 5-lipoxygenase (5-LOX). A body of work^18–24 has established that the anti-inflammatory actions, which are associated with the up-regulation of 15-LOX and/or 15S-HETE formation are mediated by LXA₄ and its G-protein coupled receptor ALX. Recent reports have demonstrated that stable analogs of LXA₄ inhibit VEGF induced angiogenic responses in endothelial cells.^25–27 These metabolically stable analogs are mimetics of aspirin-triggered LXA₄, an endogenous isomer whose synthesis can be triggered by aspirin-acetylated cyclooxygenase-2 rather than 15-LOX. This 15-epi-isomer of LXA₄ resists metabolic inactivation and mediates it bioactions, like LXA₄, via the ALX receptor. The intimate link between inflammation and angiogenesis and the ability of LXA₄²⁸ and analogs of 15-epi LXA₄^25–27 to inhibit VEGF-A induced angiogenic responses in vitro points toward a potential role of endogenous LXA₄ circuits in pathological angiogenesis. However, the endogenous role of 15-LOX in the regulation of angiogenesis remains controversial. Reports have demonstrated that the enzyme or its products promote or inhibit angiogenic responses in in vitro studies.^29–32 More importantly, the in vivo role of the 15-LOX pathway or the LXA₄ circuit in pathological neovascularization remains to be clearly defined. To this end, we assessed the role the 15-LOX pathway and LXA₄ circuit in chronic injury-induced inflammatory neovascularization.Here, we report that inflammatory neovascularization and up-regulation of the VEGF circuit correlate with changes in both 15-LOX (Alox15) and LXA₄ receptor (ALX) expression and temporally defined 15-LOX activity. More importantly, genetic deletion of 15-LOX or 5-LOX, key enzymes in the formation of LXA₄, led to amplified neovascularization and expression of VEGF-A and FLT4 in the avascular cornea during chronic injury. LXA₄, but not 15S-HETE, attenuated expression of VEGF-A and FLT4 and the angiogenic response, which provides evidence that selective autacoids from the prominent 15-LOX pathway have an endogenous role in limiting pathological neovascularization.     

Small for gestational age (SGA) neonates show reduced suppressive activity of their regulatory T cells

Little information exists concerning the role of fetal regulatory T cells (Tregs) during intrauterine development. We examined whether complications such as reduced birth weight or the occurrence of preterm labor were associated with deficiencies in the number or in the immunosuppressive activity of Tregs in the fetal circulation. Their total number did not change during normal or complicated pregnancy. In contrast, their level of FoxP3 expression decreased continuously with gestational age and was significantly reduced in the presence of spontaneous term, but not preterm labor. In small for gestational age (SGA) neonates, FoxP3 expression was constantly decreased when compared to age matched healthy neonates. In accordance with the low FoxP3 expression, the suppressive activity of the Tregs from spontaneously term delivered and from SGA babies was significantly reduced. We propose that the level of FoxP3 expression in the fetal Tregs may be a potential regulator of their suppressive activity.