The V433M variant of the CYP4F2 is associated with ischemic stroke in male Swedes beyond its effect on blood pressure

Cytochrome (CYP) 4A11 and CYP4F2 are responsible for renal production of 20-hydroxyeicosatetraenoic acid, a vasoconstrictor and natriuretic substance. The CYP4A11 F434S and CYP4F2 V433M polymorphisms reduce 20-hydroxyeicosatetraenoic acid production in vitro. The aim of the present study was to evaluate the effect of these polymorphisms on blood pressure (BP) levels, hypertension prevalence, and risk of incident cardiovascular events in middle-aged Swedes. The polymorphisms were genotyped in the cardiovascular cohort of the Malm? Diet and Cancer Study. The incidence of cardiovascular events (coronary events, n=276; ischemic stroke, n=199) was monitored over 10 years of follow-up. The analysis of BP levels was performed twice: either excluding or including subjects under antihypertensive treatment. In the whole population, CYP4A11 S434S homozygotes had higher systolic BP, both crude and adjusted for the number of antihypertensive drugs, and higher prevalence of hypertension with respect to F434 carriers. Male, but not female, CYP4F2 M433 carriers had significantly higher crude and adjusted systolic and diastolic BPs and a trend toward higher hypertension prevalence (P=0.06) with respect to V433V homozygotes. After adjustment for major cardiovascular risk factors, the hazard ratio for incident ischemic stroke in male CYP4F2 M433 carriers was significantly higher with respect to V433V homozygotes (hazard ratio: 1.69; 95% CI: 1.10 to 2.60) even when baseline BP levels and hypertension prevalence were included in the Cox proportional hazard model. A common CYP4F2 V433M polymorphism might increase the risk of incident ischemic stroke in male subjects only partially through its elevating effect on BP. Additional studies are needed to confirm these data.     

Liver-derived insulin-like growth factor-I is involved in the regulation of blood pressure in mice

IGF-I has been suggested to be of importance for cardiovascular structure and function, but the relative role of locally produced and liver-derived endocrine IGF-I remains unclear. Using the Cre-LoxP recombination system, we have previously created transgenic mice with a liver-specific, inducible IGF-I knockout (LI-IGF-I-/-). To examine the role of liver-derived IGF-I in cardiovascular physiology, liver-derived IGF-I was inactivated at 4 wk of age, resulting in a 79% reduction of serum IGF-I levels. At 4 months of age, systolic blood pressure (BP) was increased in LI-IGF-I-/- mice. Echocardiography showed increased posterior wall thickness in combination with decreased stroke volume and cardiac output, whereas other systolic variables were unchanged, suggesting that these cardiac effects were secondary to increased peripheral resistance. Acute nitric oxide-synthase inhibition increased systolic BP more in LI-IGF-I-/- mice than in control mice. LI-IGF-I-/- mice showed impaired acetylcholine-induced vasorelaxation in mesenteric resistance vessels and increased levels of endothelin-1 mRNA in aorta. Thus, the increased peripheral resistance in LI-IGF-I-/- mice might be attributable to endothelial dysfunction associated with increased expression of endothelin-1 and impaired vasorelaxation of resistance vessels. In conclusion, our findings suggest that liver-derived IGF-I is involved in the regulation of BP in mice.     

Measurement of the migration of a focal knee resurfacing implant with radiostereometry: An experimental study

Background and purpose

Articular resurfacing metal implants have been developed to treat full-thickness localized articular cartilage defects. Evaluation of the fixation of these devices is mandatory. Standard radiostereometry (RSA) is a validated method for evaluation of prosthetic migration, but it requires that tantalum beads are inserted into the implant. For technical reasons, this is not possible for focal articular resurfacing components. In this study, we therefore modified the tip of an articular knee implant and used it as a marker for RSA, and then validated the method.

Material and methods

We modified the tip of a resurfacing component into a hemisphere with a radius of 3 mm, marked it with a 1.0-mm tantalum marker, and implanted it into a sawbone marked with 6 tantalum beads. Point-motion RSA of the “hemisphere bead” using standard automated RSA as the gold standard was compared to manual measurement of the tip hemisphere. 20 repeated stereograms with gradual shifts of position of the specimen between each double exposure were used for the analysis. The tip motion was compared to the point motion of the hemisphere bead to determine the accuracy and precision.

Results

The accuracy of the manual tip hemisphere method was 0.08–0.19 mm and the precision ranged from 0.12 mm to 0.33 mm.

Interpretation

The accuracy and precision for translations is acceptable when using a small hemisphere at the tip of a focal articular knee resurfacing implant instead of tantalum marker beads. Rotations of the implant cannot be evaluated. The method is accurate and precise enough to allow detection of relevant migration, and it will be used for future clinical trials with the new implant.We have developed a double-coated monobloc articular resurfacing metal implant, with a small peg for primary fixation, to treat localized, full-thickness articular cartilage defects (Manda et al. 2011, Martinez-Carranza et al. 2013). The osseointegration of this implant after 6 and 12 months has been evaluated in animal models by several authors, with promising but varied results (Kirker-Head et al. 2006, Custers et al. 2009, Custers 2010). However, it has not yet been studied in humans. With radiostereometric analysis (RSA), it is possible to obtain highly accurate 3D measurements from calibrated stereoradiographs. By performing repeated measurements over time, implant migration can be quantified and loosening predicted with high sensitivity (Kärrholm et al. 1994, Ryd et al. 1995). The method requires the insertion of tantalum markers into the skeleton and the implant. Marking of an implant requires modification of the implant design, but it is not feasible for custom-made articular focal knee implants. To our knowledge, no other RSA study has been published on these types of components. The aim of this study was to validate point-motion RSA when applied to a new articular resurfacing metal implant used for focal cartilage knee injuries.     

Relative Validity of Micronutrient and Fiber Intake Assessed With Two New Interactive Meal- and Web-Based Food Frequency Questionnaires

Background

The meal- and Web-based food frequency questionnaires, Meal-Q and MiniMeal-Q, were developed for cost-efficient assessment of dietary intake in epidemiological studies.

Objective

The objective of this study was to evaluate the relative validity of micronutrient and fiber intake assessed with Meal-Q and MiniMeal-Q. The reproducibility of Meal-Q was also evaluated.

Methods

A total of 163 volunteer men and women aged between 20 and 63 years were recruited from Stockholm County, Sweden. Assessment of micronutrient and fiber intake with the 174-item Meal-Q was compared to a Web-based 7-day weighed food record (WFR). Two administered Meal-Q questionnaires were compared for reproducibility. The 126-item MiniMeal-Q, developed after the validation study, was evaluated in a simulated validation by using truncated Meal-Q data.

Results

The study population consisted of approximately 80% women (129/163) with a mean age of 33 years (SD 12) who were highly educated (130/163, 80% with >12 years of education) on average. Cross-classification of quartiles with the WFR placed 69% to 90% in the same/adjacent quartile for Meal-Q and 67% to 89% for MiniMeal-Q. Bland-Altman plots with the WFR and the questionnaires showed large variances and a trend of increasing underestimation with increasing intakes. Deattenuated and energy-adjusted Spearman rank correlations between the questionnaires and the WFR were in the range ρ=.25-.69, excluding sodium that was not statistically significant. Cross-classifications of quartiles of the 2 Meal-Q administrations placed 86% to 97% in the same/adjacent quartile. Intraclass correlation coefficients for energy-adjusted intakes were in the range of .50-.76.

Conclusions

With the exception of sodium, this validation study demonstrates Meal-Q and MiniMeal-Q to be useful methods for ranking micronutrient and fiber intake in epidemiological studies with Web-based data collection.     

Rotational atherectomy with a new device: Initial clinical experience

The Bard Atherectomy Catheter is a new rotational atherectomy device that consists of a flexible, hollow, thin-walled cutting catheter that, while rotated at 1,500 revolutions per minute, is advanced across the lesion over a special spiral guidewire system. We report the initial clinical experience with this device in 20 peripheral lesions in ten patients. The majority of patients were treated for limb salvage. All lesions were successfully intervened on by atherectomy followed by adjunctive balloon angioplasty. A reduction to less than 50% stenosis was achieved in 13 of the 20 lesions (65%) after atherectomy but in all 20 lesions (100%) after adjunctive angioplasty for all lesions and stenting for dissections in two. Baseline minimal lesion lumen diameter was 0.8 ± 0.7 mm with a reference vessel diameter of 4.2 ± 1.7 mm (75 ± 21% stenosis). The lumen improved to 2.0 ± 0.8 mm (45 ± 19% stenosis) (P < 0.001) following atherectomy and to 3.9 ± 1.9 mm (13 ± 16% stenosis) (P < 0.001) after adjunctive angioplasty. The average weight of removed atheroma was 45 ± 58 mg. All ten patients had initial improvement in symptoms. At 6 months follow-up there was persistent improvement in eight patients and two subjects had undergone amputations. Our early clinical experience with this low profile, flexible atherectomy device, that enables extraction of a large amount of atheroma, suggests that it will become a valuable addition to current atherectomy technologies in small- and medium-sized vessels. The value of this device in coronary vessels is under investigation. © 1996 Wiley-Liss, Inc.     

Isolation of myelinoid Marchi-positive bodies from normal rabbit spinal cord

Normal rabbit spinal cord was homogenized in sucrose and fractionated by centrifugation in a sucrose density gradient system slightly modified after the Norton-Poduslo method for the isolation of myelin. The following fractions were recovered: the fraction floating on 0.32 M sucrose, the myelin fraction at the 0.32 M/0.85 M interface and the pellet. After fixation in glutaraldehyde the fractions were subjected to Marchi staining, a histochemical method used for the demonstration of degenerating myelin. The floating fraction was enriched in Marchi-positive bodies as compared to the homogenate while the myelin fraction and the pellet contained low amounts. No esterified cholesterol was found in the floating fraction. Since histochemical and electron microscopical studies have shown that Marchi-positive myelinoid bodies in the normal CNS are associated with node-paranode regions our results indicate a possibility to isolate and biochemically characterize a presumably closely myelin-related fraction of known anatomical origin. The absence of esterified cholesterol in the floating fraction shows that biochemical or biophysical properties other than a content of esterified cholesterol may give rise to a positive Marchi reaction.