ADAMTS-7 Modulates Atherosclerotic Plaque Formation by Degradation of TIMP-1.

BACKGROUND: The ADAMTS7 locus was genome-wide significantly associated with coronary artery disease. Lack of the ECM (extracellular matrix) protease ADAMTS-7 (A disintegrin and metalloproteinase-7) was shown to reduce atherosclerotic plaque formation. Here, we sought to identify molecular mechanisms and downstream targets of ADAMTS-7 mediating the risk of atherosclerosis. METHODS: Targets of ADAMTS-7 were identified by high-resolution mass spectrometry of atherosclerotic plaques from Apoe-/- and Apoe-/-Adamts7-/- mice. ECM proteins were identified using solubility profiling. Putative targets were validated using immunofluorescence, in vitro degradation assays, coimmunoprecipitation, and Förster resonance energy transfer-based protein-protein interaction assays. ADAMTS7 expression was measured in fibrous caps of human carotid artery plaques. RESULTS: In humans, ADAMTS7 expression was higher in caps of unstable as compared to stable carotid plaques. Compared to Apoe-/- mice, atherosclerotic aortas of Apoe-/- mice lacking Adamts-7 (Apoe-/-Adamts7-/-) contained higher protein levels of Timp-1 (tissue inhibitor of metalloprotease-1). In coimmunoprecipitation experiments, the catalytic domain of ADAMTS-7 bound to TIMP-1, which was degraded in the presence of ADAMTS-7 in vitro. ADAMTS-7 reduced the inhibitory capacity of TIMP-1 at its canonical target MMP-9 (matrix metalloprotease-9). As a downstream mechanism, we investigated collagen content in plaques of Apoe-/- and Apoe-/-Adamts7-/- mice after a Western diet. Picrosirius red staining of the aortic root revealed less collagen as a readout of higher MMP-9 activity in Apoe-/- as compared to Apoe-/- Adamts7-/- mice. To facilitate high-throughput screening for ADAMTS-7 inhibitors with the aim of decreasing TIMP-1 degradation, we designed a Förster resonance energy transfer-based assay targeting the ADAMTS-7 catalytic site. CONCLUSIONS: ADAMTS-7, which is induced in unstable atherosclerotic plaques, decreases TIMP-1 stability reducing its inhibitory effect on MMP-9, which is known to promote collagen degradation and is likewise associated with coronary artery disease. Disrupting the interaction of ADAMTS-7 and TIMP-1 might be a strategy to increase collagen content and plaque stability for the reduction of atherosclerosis-related events.

Fragmentomic analysis of circulating tumor DNA-targeted cancer panels.

BACKGROUND: The isolation of cell-free DNA (cfDNA) from the bloodstream can be used to detect and analyze somatic alterations in circulating tumor DNA (ctDNA), and multiple cfDNA-targeted sequencing panels are now commercially available for Food and Drug Administration (FDA)-approved biomarker indications to guide treatment. More recently, cfDNA fragmentation patterns have emerged as a tool to infer epigenomic and transcriptomic information. However, most of these analyses used whole-genome sequencing, which is insufficient to identify FDA-approved biomarker indications in a cost-effective manner. PATIENTS AND METHODS: We used machine learning models of fragmentation patterns at the first coding exon in standard targeted cancer gene cfDNA sequencing panels to distinguish between cancer and non-cancer patients, as well as the specific tumor type and subtype. We assessed this approach in two independent cohorts: a published cohort from GRAIL (breast, lung, and prostate cancers, non-cancer, n = 198) and an institutional cohort from the University of Wisconsin (UW; breast, lung, prostate, bladder cancers, n = 320). Each cohort was split 70%/30% into training and validation sets. RESULTS: In the UW cohort, training cross-validated accuracy was 82.1%, and accuracy in the independent validation cohort was 86.6% despite a median ctDNA fraction of only 0.06. In the GRAIL cohort, to assess how this approach performs in very low ctDNA fractions, training and independent validation were split based on ctDNA fraction. Training cross-validated accuracy was 80.6%, and accuracy in the independent validation cohort was 76.3%. In the validation cohort where the ctDNA fractions were all <0.05 and as low as 0.0003, the cancer versus non-cancer area under the curve was 0.99. CONCLUSIONS: To our knowledge, this is the first study to demonstrate that sequencing from targeted cfDNA panels can be utilized to analyze fragmentation patterns to classify cancer types, dramatically expanding the potential capabilities of existing clinically used panels at minimal additional cost.

Invasive annuals respond more negatively to drought than native species.

In his foundational list of 'ideal weed' characteristics, Baker (1965) proposed that weedy plants maximize reproductive output under high resource availability. Since then, the idea that invasive plant species are more responsive to fluctuating resources compared with native or noninvasive species has gained considerable traction, although few studies extend this hypothesis to include reproductive output. We revisit Baker's hypothesis in the context of invasion and drought in California grasslands, exploring whether invasives show greater growth and reproductive responses to water availability compared with the native wildflowers they displace. In an outdoor potted study, we grew eight native and eight invasive species of annuals commonly found in southern California grasslands to reproductive maturity under both well-watered and drought conditions. While drought negatively impacted plant performance overall, invasives showed more negative responses for growth and reproductive traits. Invasives also grew larger than native species, especially under well-watered conditions, and produced seed with higher rates of germination. Invasives may be more negatively impacted by drought compared with natives, but they are also able to capitalize on high resource conditions and greatly increase reproductive output. Such opportunistic responses exhibited by invasives might explain previously observed fluctuations in their abundance under variable precipitation.

Can we condition native plants to increase drought tolerance and improve restoration success?

A common method in ecological restoration is the transplanting of nursery-grown seedlings to the field and, with proper resources, this technique can be highly successful. However, stressors such as drought may negatively impact plant performance and restoration success, especially in dryland ecosystems. Furthermore, increasing environmental change may hamper the ability of practitioners to restore native vegetation. A growing body of research suggests that exposing plants to a stressor may improve tolerance to subsequent stress events later in life. We sought to understand if such a phenomenon could be exploited in order to improve plant drought-tolerance and aid native plant restoration in southern California. In a multi-phase experiment, we first exposed seedlings of native perennials to episodic drought and then later compared the response of these plants to a second drought event to that of well-watered controls. We also transplanted replicates of both treatments to a restoration site in the field to test whether exposure to drought as a seedling could improve plant performance. Plant species responded to drought differently, with species exhibiting the full range of positive, neutral, and negative responses to temporal variability in water stress. However, some species appeared to benefit from drought preconditioning, exhibiting greater growth and increased water-use efficiency compared to well-watered plants. This suggests that simple applications of stress treatments could improve plant growth and stress tolerance, but the success of this method is likely very species specific. Restoration practitioners should consider conducting pilot studies with target plant species to better understand if this technique could assist in achieving restoration goals.

Clinical and laboratory evaluation of cured and non-cured patients with cutaneous leishmaniasis treated by Glucantime.

BACKGROUND & OBJECTIVES: Insufficient treatment of cutaneous leishmaniasis (CL) by conventional drugs is a major barrier in control strategies. This study was aimed to evaluate Glucantime efficacy and the susceptibility of Glucantime unresponsive and responsive CL isolates in the field and laboratory. METHODS: Chi-square test (x[2]) was used to determine the significance of difference between proportions in Glucantime-treated patients. The inhibitory activity of various concentrations of Glucantime against Leishmenia tropica stages was evaluated by a colorimetric cell viability MTT and macrophage assays. Mixed model, t-test and ANOVA were performed to determine the significance of difference between various concentrations of Glucantime unresponsive or responsive isolates and untreated control group and p <0.05 was defined as significant level. Altogether, 89.8% of the patients were cured by Glucantime, whilst 10.2% remained non-cured. RESULTS: The overall Glucantime efficacy in different age groups and genders was similar. The IC50 values of promastigotes and amastigotes for Glucanime unresponsive isolates were 2.1 and 2.6 times higher than the equivalent rates obtained for responsive cases, respectively. The overall mean number of amastigotes within macrophages in unresponsive isolates was significantly higher (32.68 ± 1.24) than that in responsive ones (18.68 ± 1.52, p <0.001). Glucantime unresponsive and responsive field isolates of anthroponotic CL (ACL) caused by L. tropica strongly correlated to in vitro assays. INTERPRETATION & CONCLUSION: Monitoring of Glucantime unresponsiveness by the health surveillance system is extremely important, where anthroponotic transmission occurs in humans. Hence, physicians should be aware of such clinical unresponsive presentations with ACL for antimonial therapeutic failure to improve management of disease in endemic regions.

The effect of grapeseed oil on performance, rumen fermentation, antioxidant status and subcutaneous adipose fatty acid profile in lambs.

This experiment was carried out to examine the effect of grapeseed oil (GSO) on performance, rumen fermentation, antioxidant status and subcutaneous adipose fatty acid (FA) profile in lambs. Eighteen Baluchi lambs, 196 ± 14 days of age and 39.8 ± 1.7 kg body weight, were randomly assigned to three experimental diets: (i) diet without GSO (control), (ii) diet containing 2% of GSO (GSO2) and (iii) diet containing 4% of GSO (GSO4) for 42 days. Results showed that the experimental diets had no significant effect on dry matter intake and performance (p > 0.05). The supplemented diets with GSO had no effect on pH and NH3 -N of rumen fluid (p > 0.05), but GSO4 increased (p = 0.003) the concentration of propionic acid and reduced (p = 0.002) the concentration of acetate acid compared to the control. Inclusion 4% of GSO to the diet increased total antioxidant activity and decreased malondialdehyde in serum and muscle (p < 0.001). The level of blood glutathione peroxidase in diets containing GSO was higher than control diet (p = 0.02), but diets had no effect on superoxide dismutase in blood and muscle tissues (p > 0.05). The concentration of vaccenic acid, rumenic acid and linoleic acid and thus polyunsaturated fatty acid in subcutaneous fat was affected by experimental diets (p < 0.001), as control had the lowest amount of these FAs and GSO4 had the highest amount of them. Therefore, it can be concluded that the use of GSO up to 4% improves the antioxidant status and adipose fatty acid profile in lambs without effects on performance.

The Effect of increasing levels of date palm (Phoenix dactylifera L.) seed on the performance, ruminal fermentation, antioxidant status and milk fatty acid profile of Saanen dairy goats.

This study was conducted to examine the effect of date palm (Phoenix dactylifera L.) seed (DPS) on the performance, ruminal fermentation, antioxidant status and milk fatty acid (FA) profile of dairy goats. Eight multiparous Saanen dairy goats, averaging 97 ± 7 days in milk (DIM) and 2150 ± 130 g of milk production, were used in a 4 × 4 replicated Latin square design. Experimental diets contained 0% (control), 6% (DPS6), 12% (DPS12) and 18% (DPS18) of DPS. Dry matter intake (DMI), milk production, and the composition and digestibility of the dry matter (DM), organic matter (OM), neutral detergent fibre (NDF) and crude protein (CP) were not affected by the diets. Adding DPS to the diet increased linearly total antioxidant capacity (TAC) in milk and blood (p < 0.05). No significant difference was found in the malondialdehyde (MDA) content in milk and blood. Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in the blood, ruminal pH, NH3 -N, ruminal total volatile fatty acid (VFA), acetate, butyrate, isovalerate and valeric acid concentration had no significant effect among the diets. The propionate acid concentration decreased linearly as DPS was added to the diet, and DPS18 had minimum propionate acid concentration (p < 0.05). The inclusion of DPS18 to diets increased linearly the proportion of C18:0 (compared to control) as well as cis-18:1, trans-18:1 (compared to control and DPS6) and decreased C14:1 (compared to control) in milk fat (p < 0.05). The concentration of conjugated linoleic acid (CLA) in DPS18 was higher than other diets (p = 0.04). The results of this study implied that replacing DPS with a part of dairy goats' ration had no negative effects on the performance of the animals and could also improve the antioxidant activity and increase the concentration of CLA in their milk.

Antioxidant supplementation of low-protein diets reduced susceptibility to pulmonary hypertension in broiler chickens raised at high altitude.

A reduced-protein diet (designated as RPD) was prepared and its effects on growth performance and the development of pulmonary hypertension syndrome (PHS) were evaluated in broiler chickens compared to a normal-protein diet (designated as NPD) or to the RPD supplemented with CoQ10 alone (30 mg/kg) or in combination with vitamin E (30 mg/kg CoQ10 + 100 mg/kg vitamin E). The RPD had 30 g/kg less crude protein compared to the NPD. A total of 208 1-day-old male broilers (Ross 308 strain) were used in a 42-day trial. Serum concentrations of uric acid (UA) and nitric oxide (NO) significantly (p < 0.05) declined when chickens fed on the RPD. However, supplementing RPD with the antioxidants significantly (p < 0.05) increased the serum NO concentration. Although serum malondialdehyde (MDA) concentration was significantly (p < 0.05) higher in the RPD than the NDP, supplementing RPD with CoQ10 and CoQ10 + VE decreased serum MDA concentration to similar levels found in the NPD. Significant overexpression in GPX1 gene observed in the heart and lungs of broilers fed on the RPD, which was effectively restored by supplementation of CoQ10 . The right to total ventricular weight ratio (RV:TV) was significantly (p < 0.05) increased in birds fed the RPD, which concurred with an increase in mortality from pulmonary hypertension syndrome (PHS). However, a significant decline in mortality from PHS was observed when birds on RPD received CoQ10 or CoQ10 + VE. In conclusion, antioxidant supplementation effectively improves pulmonary hypertensive response in broiler chicken fed of reduced-protein diets.

On a derivative-free variant of king's family with memory.

The aim of this paper is to construct a method with memory according to King's family of methods without memory for nonlinear equations. It is proved that the proposed method possesses higher R-order of convergence using the same number of functional evaluations as King's family. Numerical experiments are given to illustrate the performance of the constructed scheme.

On a cubically convergent iterative method for matrix sign.

We propose an iterative method for finding matrix sign function. It is shown that the scheme has global behavior with cubical rate of convergence. Examples are included to show the applicability and efficiency of the proposed scheme and its reciprocal.

L-arginine supplementation of reduced-protein diets improves pulmonary hypertensive response in broiler chickens reared at high altitude.

This study was conducted at high altitude (2100 m above sea level). A total of 208 d-old male broilers (Ross 308) were randomised across 16 floor pens and reared up to 42 d. A normal-protein diet (NPD) was formulated according to the National Research Council. A reduced-protein diet (RPD) was prepared with dietary protein reduced by 30 g/kg relative to that of the NPD. Two additional diets were prepared by adding 2 and 4 g L-arginine (ARG)/kg to the RPD. At the end of trial (42 d), blood sampling was done and carcass characteristics were recorded. ARG supplementation of the RPD at 4 g improved feed:gain in the growing stage and throughout the trial compared with the RPD. The right-to-total ventricular weight ratio was significantly increased in birds fed on RPD compared with those fed on NPD or ARG-supplemented RPD. Feeding RPD caused a significant decrease in plasma concentrations of nitric oxide (NO) and uric acid. Plasma NO level, however, was restored by ARG supplementation of RPD. ARG supplementation of RPD, however, significantly reduced the rate of pulmonary hypertension syndrome mortality compared to the negative control fed on RPD.

Cardiovascular disease risk factors in the South Asian population living in Kuwait: a cross-sectional study.

BACKGROUND: High rates of diabetes and cardiovascular disease have been reported in South Asian immigrants in many countries. However, the prevalence and characteristics of cardiovascular disease risk factors among a South Asian population living in Kuwait have not yet been investigated. This study was therefore designed to estimate the prevalence of cardiovascular disease risk factors and determine whether they are independently associated with diabetes in such a population. METHODS: A population-based cross-sectional study was conducted on 1094 South Asians (781 men and 313 women), mainly Indian and Pakistani (≥ 18 years of age), of whom 75.1% were Indians. Interviews were carried out, during which socio-demographic and anthropometric data were collected, followed by a physical examination and collection of fasting blood samples for laboratory investigations. Diabetes was defined by fasting plasma glucose ≥ 7 mmol/l, or being on treatment, and/or self-reported previously diagnosed Type 2 diabetes. RESULTS: The prevalence of diabetes was 21.1%, with 3.4% of that percentage of people being newly diagnosed. Using BMI measurements, 24.0% of those who participated in the study were obese and 46.1% were overweight. Dyslipidaemia was found in 77.6% and hypertension in 44.8%. Advancing age (≥ 40 years), male gender, high LDL, high total cholesterol, hypertension and positive family history of diabetes were significantly associated with increased risk of diabetes. CONCLUSION: Our study shows that the prevalence of cardiovascular disease risk factors in South Asian expatriates in Kuwait exceeds prevalence rates reported in their homeland and other countries. This may suggest the added stress of environmental factors on the development of cardiovascular disease risk factors in such populations. Specialized prevention programmes targeting such high-risk ethnic populations are paramount and need to be implemented.

On a new iterative scheme without memory with optimal eighth order.

The purpose of this paper is to derive and discuss a three-step iterative expression for solving nonlinear equations. In fact, we derive a derivative-free form for one of the existing optimal eighth-order methods and preserve its convergence order. Theoretical results will be upheld by numerical experiments.

Effect of congenital ptosis on corneal topography and total aberrometry and comparison of these variables between ptotic and normal fellow eyes.

PURPOSE: To analyze the effect of congenital ptosis on corneal topography and total aberrometry and to compare these variables between ptotic and normal fellow eyes. METHODS: The study included 32 eyes of 16 patients with unilateral congenital blepharoptosis. A Shack-Hartmann wavefront sensor was employed to assess Zernike coefficients and root-mean-square. Computerized corneal topography, Orbscan and aberrometry were measured in the healthy and ptotic eyes. Data were analyzed using SPSS version 16. P<0.05 was considered significant. RESULTS: The mean patient age was 21.31±6.3 years. The mean margin to light reflex distance-1 (MRD-1) was 0.6±1.44mm in the ptotic eyes. Among topography variables, surface regularity index (SRI), cylinder power, irregular astigmatism index (IAI), and flat meridian keratometry were significantly different between ptotic and non-ptotic fellow eyes (P<0.05). Some Orbscan parameters, including simulated keratometry, maximum and minimum corneal power, and astigmatism power were significantly different between ptotic and normal fellow eyes (P<0.05). There was no statistically significant difference in total aberrometry variables between paired eyes. However, in a comparison between ptotic eyes with over 1 diopter astigmatism vs. less than 1 D, high-order Zernike modes without spherical aberration at 6mm (HOW/O Z400 6mm) were significantly different between the 2 groups (P=0.02). CONCLUSION: Unilateral congenital ptosis significantly affects corneal topography and aberrometry, especially in eyes with astigmatism≥1 D. Such differences need to be considered before keratorefractive surgery (KRS).

Targeting Unique Ligand Binding Domain Structural Features Downregulates DKK1 in Y537S ESR1 Mutant Breast Cancer Cells.

Resistance to endocrine therapies remains a major clinical hurdle in breast cancer. Mutations to estrogen receptor alpha (ERα) arise after continued therapeutic pressure. Next generation selective estrogen receptor modulators and degraders/downregulators (SERMs and SERDs) show clinical efficacy, but responses are often non-durable. A tyrosine to serine point mutation at position 537 in the ERα ligand binding domain (LBD) is among the most common and most pathogenic alteration in this setting. It enables endocrine therapy resistance by superceding intrinsic structural-energetic gatekeepers of ER hormone-dependence, it enhances metastatic burden by enabling neomorphic ER-dependent transcriptional programs, and it resists SERM and SERD inhibiton by reducing their binding affinities and abilities to antagonize transcriptional coregulator binding. However, a subset of SERMs and SERDs can achieve efficacy by adopting poses that force the mutation to engage in a new interaction that favors the therapeutic receptor antagonist conformation. We previously described a chemically unconventional SERM, T6I-29, that demonstrates significant anti-proliferative activities in Y537S ERα breast cancer cells. Here, we use a comprehensive suite of structural-biochemical, in vitro, and in vivo approaches to better T6I-29's activities in breast cancer cells harboring Y537S ERα. RNA sequencing in cells treated with T6I-29 reveals a neomorphic downregulation of DKK1, a secreted glycoprotein known to play oncogenic roles in other cancers. Importantly, we find that DKK1 is significantly enriched in ER+ breast cancer plasma compared to healthy controls. This study shows how new SERMs and SERDs can identify new therapeutic pathways in endocrine-resistant ER+ breast cancers.

Targeting Unique Ligand Binding Domain Structural Features Downregulates DKK1 in Y537S ESR1 Mutant Breast Cancer Cells.

Resistance to endocrine therapies remains a major clinical hurdle in breast cancer. Mutations to estrogen receptor alpha (ERα) arise after continued therapeutic pressure. Next generation selective estrogen receptor modulators and degraders/downregulators (SERMs and SERDs) show clinical efficacy, but responses are often non-durable. A tyrosine to serine point mutation at position 537 in the ERα ligand binding domain (LBD) is among the most common and most pathogenic alteration in this setting. It enables endocrine therapy resistance by superceding intrinsic structural-energetic gatekeepers of ER hormone-dependence, it enhances metastatic burden by enabling neomorphic ER-dependent transcriptional programs, and it resists SERM and SERD inhibiton by reducing their binding affinities and abilities to antagonize transcriptional coregulator binding. However, a subset of SERMs and SERDs can achieve efficacy by adopting poses that force the mutation to engage in a new interaction that favors the therapeutic receptor antagonist conformation. We previously described a chemically unconventional SERM, T6I-29, that demonstrates significant anti-proliferative activities in Y537S ERα breast cancer cells. Here, we use a comprehensive suite of structural-biochemical, in vitro, and in vivo approaches to better T6I-29's activities in breast cancer cells harboring Y537S ERα. RNA sequencing in cells treated with T6I-29 reveals a neomorphic downregulation of DKK1, a secreted glycoprotein known to play oncogenic roles in other cancers. Importantly, we find that DKK1 is significantly enriched in ER+ breast cancer plasma compared to healthy controls. This study shows how new SERMs and SERDs can identify new therapeutic pathways in endocrine-resistant ER+ breast cancers.

Diabetes and associated cardiovascular risk factors in the State of Kuwait: the first national survey.

BACKGROUND: Cardiovascular diseases (CVD) are the leading cause of mortality worldwide as well as in Kuwait. People with diabetes have two to five times greater risk of developing CVD as compared with non-diabetic individuals. To date, little information exists on the prevalence and characteristics of cardiovascular risk factors in Kuwait. The objective of this survey was to address the growing burden of diabetes and related cardiovascular risk factors, and to estimate, for the first time, the prevalence of cardiovascular risk factors in the State of Kuwait. METHODS: The study was carried out using the World Health Organization (WHO) STEPwise approach for surveillance of non-communicable disease risk factors. This study represents a national survey for Kuwaiti nationals aged between 20 and 65 years. All participants were involved in an interview for gathering sociodemographic information, underwent focused physical examination and donated a blood sample for the study-specific laboratory investigations. RESULTS: A total of 1970 subjects, with a mean age of 48.9 ± 10.5, were screened. The prevalence of cardiovascular risk factors was as follows: diabetes 17.9%, dyslipidaemia 70.3%, hypertension 25.3% and obesity 48.2%. Over 62% had a sedentary lifestyle, and 17.8% were smokers. The prevalence of diabetes and dyslipidaemia increased with age and body mass index. Diabetes was also significantly associated with age above 40 years (OR = 10.5), family history of diabetes (OR = 2.79), hypertension (OR = 2.22), obesity (OR = 2.87) and lower literacy (OR = 4.23). CONCLUSIONS: This study found that advancing age (≥ 40 years), diabetes mellitus, obesity, positive family history of diabetes, hypertension and dyslipidaemia are significant risk factors for developing CVD in Kuwait as in other parts of the world. Understanding these factors allows for preventive measures to be taken for Kuwaiti population.

Plasticity in Compensatory Growth to Artificial Defoliation and Light Availability in Four Neotropical Understory and Forest Edge Herb Species.

Defoliation from falling branches is a major factor in the survival of understory herbs in tropical rainforests. Experimental studies of defoliation under three levels of light environment compared responses to partial and total defoliation in four species of tropical rainforest understory herbs. We predicted that elevated levels of light availability would help compensate for damage to through compensatory growth in both understory and forest edge species and that forest edge species would more effectively compensate under high light conditions than shade-tolerant species from the forest understory All species showed a high tolerance to defoliation under high and intermediate light conditions. Under low-light conditions survival differed dramatically with minimal mortality in forest-edge species compared to high mortality in completely defoliated understory species. Defoliation, and light × defoliation interactions, impacted multiple growth traits in understory species. In contrast, forest-edge species showed no effect of defoliation except on total biomass, and only one light × defoliation interaction was observed. Our results indicate that differences in biomass allocation, leaf ecophysiology, and other growth parameters between forest understory and edge species may be structuring post-damage response in understory and forest edge herbs.

Median aperture of the fourth ventricle revisited.

BACKGROUND: The median aperture of Magendie is the largest of three openings of the fourth ventricle and thus it forms the main path for the outflow of the cerebrospinal fluid from the ventricle. The Magendie aperture connects the fourth ventricle with the cisterna magna and makes a natural corridor for neurosurgical approach and inspection of the ventricle and its floor. The purpose of this study was to give a contemporary anatomical view of this structure in the context of historical data. MATERIAL AND METHODS: The Magendie foramen was studied in 30 fixed specimens of human brainstems with cerebella. The microdissection technique was used. Measurements were taken with a microscope ocular ruler. RESULTS: The aperture is limited by the following structures: obex and gracile tubercles inferiorly, and tela choroidea with choroid plexus superolaterally. Obex tubercles usually have the form of a piece of neural tissue bridging two halves of the brainstem above the entrance to the central canal. Gracile tubercles together are 8.15 mm wide and the maximal width of the foramen is 6.53 mm. Tela choroidea attaches laterally at both sides to the inferior medullary velum. In most cases the right and left choroid plexus are connected to each other with a triangular membrane of tela choroidea, which protrudes through the median foramen and attaches to the vermis at a highly variable level. CONCLUSIONS: We hope that the presented description of anatomical relations around the Magendie aperture, with its new measurements, will be helpful for those operating in the area and will explain some of the inaccuracies found in literature.

Knee flexion angle and muscle activations control the stability of an anterior cruciate ligament deficient joint in gait.

Anterior cruciate ligament (ACL) is a primary structure and a commonly injured ligament of the knee joint. Some patients with ACL deficiency (ACLD) experience joint instability and require a reconstructive surgery to return to daily routines, some can adapt by limiting their activities while others, called copers, can return to high-level activities with no instability. We investigated the effects of alterations in the knee flexion angle (KFA) and muscle force activations on the stability and biomechanics of ACLD joints at 25, 50, and 75% periods of gait stance. ACLD joint stability is controlled by variations in both KFA and knee muscle forces. For the latter, a parameter called activity index is defined as the ratio of forces in ACL antagonists (quadriceps and gastrocnemii) to those in ACL agonists (hamstrings). Under a greater KFA (2-6° beyond the mean of reported values in healthy subjects), an ACLD joint regains its pre-injury stability levels. The ACLD joint stability also markedly improves at smaller quadriceps and larger hamstrings forces (activity indices of 2.0-3.6 at 25%) at the first half of stance and smaller gastrocnemii and larger hamstrings forces (activity indices of 0.1-1.1 at 50% and 0.1-1.2 at 75%) at the second half of stance. Activity index and KFA are both crucial when assessing the dynamic stability of an ACLD joint. These results are helpful in our understanding of the biomechanics and stability of ACLD joints towards improved prevention and treatment strategies.