Minimally invasive percutaneous plate osteosynthesis for ankle fractures: a prospective observational cohort study

Background

The gold standard for the surgical management of ankle fractures is through open reduction and internal fixation. The rate of wound problems has been reported to be as high as 18 %, especially in patients with poor vascular supply or in diabetics. Minimally invasive percutaneous plate osteosynthesis (MIPPO) has been described as a potential solution for these patients.

Patients and methods

This is a prospective observational cohort study. From October 2009 to February 2010, and following ethical approval of our research, adult patients admitted at our level I trauma center with a closed lateral malleolar displaced unstable fracture (Lauge-Hansen supination-external rotation) with or without a medial-sided injury and patients with an undisplaced fracture associated with medial clear space opening on external rotation stress radiographs were recruited and managed using MIPPO technique. All patients were followed up for a minimum of 12 months post-surgery (12–20 with a mean of 16.5 months). Trauma mechanism, comorbidities, classifications, trauma-surgery interval, image intensifier duration, surgery duration, complications, and function American Orthopaedic Foot and Ankle Society (AOFAS) were analyzed.

Results

Thirty-two patients were recruited of which 20 fulfilled the inclusion criteria (16 females, 4 males) and were available for follow-up. Ten fractures (50 %) were classified as 44-B1, 7 fractures (35 %) as 44-B2, and 3 fractures (15 %) as 44-B3 according to the Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association classification (100 % were supination-external rotation injuries). At 8 weeks post-surgery, all fractures had healed. The duration of surgery ranged between 15 and 73 min (average 32.8) from skin incision to closure. There were 2 complications (1 malunion and 1 skin necrosis requiring implant removal). At 12-month follow-up, AOFAS average was 88.3 (72–100 standard deviation of 6.8 points).

Conclusion

MIPPO technique proved to be a viable option for lateral malleolar fracture treatment with a low complication rate and high functional outcome at 1 year. It is particularly useful in patients with a high risk of wound complication.     

Effect of opicapone and entacapone upon levodopa pharmacokinetics during three daily levodopa administrations

Background and objectives

Opicapone is a novel third generation catechol-O-methyltransferase (COMT) inhibitor. The purpose of this study was to compare the levodopa pharmacokinetic profile throughout a day driven by the COMT inhibition either following repeated doses of opicapone or concomitant administration with entacapone.

Methods

A randomized, double-blind, gender-balanced, parallel-group study was performed in 4 groups of 20 healthy subjects each. Four subjects in each group received placebo during the entire study. Sixteen subjects in one group received placebo once daily for 11 days and on day 12, 200 mg entacapone concomitantly with each levodopa/carbidopa dose (three times separated by a 5-h interval). Sixteen subjects in each of the remaining three groups received respectively 25, 50, and 75 mg opicapone once daily for 11 days and on day 12, placebo concomitantly with each levodopa/carbidopa dose.

Results

Levodopa minimum plasma concentration (C_min) for each levodopa/carbidopa dose and for the mean of all levodopa/carbidopa doses increased substantially with all active treatments (entacapone and opicapone) when compared to the control group (placebo), with values ranging from 1.7-fold (200 mg entacapone) to 3.3-fold (75 mg opicapone). No statistical difference was found for levodopa peak of systemic exposure (as assessed by maximum observed plasma concentration (C_max)) between all active treatments and placebo. A significant increase in the levodopa extent of systemic exposure (as assessed by concentration-time curve (AUC)) occurred with all opicapone treatments in relation to placebo. No statistical difference was found for levodopa AUC when entacapone was compared to placebo. When compared to entacapone, both 50 and 75 mg opicapone presented a significant increase for the levodopa AUC. All active treatments significantly inhibited both peak (as assessed by E_max) and extent (as assessed by effect-time curve (AUEC)) of the COMT activity in relation to placebo. When compared to entacapone, all opicapone treatments significantly decreased the extent (AUEC) of the COMT activity due to a long-lasting and sustained effect. The tolerability profile was favorable for all active treatments.

Conclusion

Opicapone, a novel third generation COMT inhibitor, when compared to entacapone, provides a superior response upon the bioavailability of levodopa associated to more pronounced, long-lasting, and sustained COMT inhibition. The tolerability profile was favorable. On the basis of the results presented in this study and along with the earlier pharmacology studies, it is anticipated that opicapone adjunct therapy at the dosages of 25 and 50 mg will provide an enhancement in levodopa availability that will translate into clinical benefit for Parkinson’s disease patients.     

Medial prefrontal cortex Transient Receptor Potential Vanilloid Type 1 (TRPV1) in the expression of contextual fear conditioning in Wistar rats

Rationale

Contextual fear is evoked by re-exposing an animal to an environment that has been previously paired with an aversive or unpleasant stimulus. It can be assessed by freezing and cardiovascular changes such as increase in mean arterial pressure and heart rate. A marked increase in neuronal activity is associated with contextual fear conditioning, especially in limbic structures involved with defense reactions, such as the ventral portion of medial prefrontal cortex.

Objective

Given the fact that transient receptor potential vanilloid type 1 (TRPV1) receptors could be involved in the expression of defensive behavior, the present work tested the hypothesis that TRPV1 manipulation in the ventromedial prefrontal cortex (vMPFC) modulates the expression of contextual conditioned fear.

Methods

Male Wistar rats received bilateral microinjections into the vMPFC of the TRPV1 receptor antagonists capsazepine (1, 10, and 60 nmol/200 nL) or 6-iodonordihydrocapsaicin (3 nmol/200 nL), and the TRPV1 agonist capsaicin (1 nmol/200 nL) preceded by vehicle or 6-iodonordihydrocapsaicin before re-exposure to the experimental chamber for 10 min, 48 h after conditioning in two different protocols distinct by their aversiveness.

Results

Both antagonists reduced the freezing and cardiovascular responses in the high aversive protocol. Capsaicin caused an increase in fear-associated responses that could be blocked by 6-iodonordihydrocapsaicin.

Conclusions

Our results indicate that TRPV1 receptors located in the vMPFC have a tonic involvement in the modulation of the expression of contextual fear conditioning.     

Critical role of nitric oxide in the modulation of prepulse inhibition in Swiss mice

Rationale

Nitric oxide (NO) modulates the dopamine uptake and release processes and appears to be implicated in dopamine-related pathologies, such as schizophrenia. However, it is unclear whether there is excess or deficient NO synthesis in schizophrenia pathophysiology. Analyses of the intracellular pathways downstream of NO system activation have identified the cyclic nucleotide cyclic guanosine monophosphate (cGMP) as a possible target for drug development. Defects in the sensorimotor gating of the neural mechanism underlying the integration and processing of sensory information have been detected across species through prepulse inhibition (PPI).

Objectives

The aim of this study was to investigate the effects of NO/cGMP increase on sensorimotor gating modulation during dopamine hyperfunction.

Methods

Mice were treated with NO donors and subjected to the PPI test. Treatment with the NO donor sodium nitroprusside was preceded by pretreatment with a soluble guanylate cyclase (sGC) inhibitor. Additionally, the mice were treated with NO donors and phosphodiesterases inhibitors prior to amphetamine treatment.

Results

Pretreatment with the NO donors enhanced the PPI response and attenuated the amphetamine-disruptive effects on the PPI. The sGC inhibitor did not modify the sodium nitroprusside effects. Additionally, the cGMP increase induced by a specific phosphodiesterase inhibitor did not modify the amphetamine-disruptive effect.

Conclusions

This study provides the first demonstration that an increase in NO can improve the PPI response and block the amphetamine-disruptive effects on the PPI response. Our data are consistent with recent clinical results. However, these effects do not appear to be related to an increase in cGMP levels, and further investigation is thus required.     

Homocysteine and nitrite levels are modulated by MTHFR 677C>T polymorphism in obese women treated with simvastatin

Higher homocysteine (Hcy) levels are associated with cardiovascular risk. The aim of the present study was to evaluate the effect of simvastatin treatment on circulating Hcy levels in obese women without hypertension, diabetes or dyslipidaemia; and to determine whether the 677C>T polymorphism located in methylenetetrahydrofolate reductase (NAD(P)H) (MTHFR) gene modulates the effects of this treatment on Hcy and nitrite (as a biomarker of nitric oxide (NO) bioavailability). Twenty‐five obese women (body mass index ≥ 30 kg/m²) who had received 20 mg/day simvastatin for 6 weeks were enrolled in the study. Venous blood samples were collected to measure plasma biomarkers and gene polymorphisms. Simvastatin treatment significantly reduced total cholesterol, low‐density lipoprotein–cholesterol, thiobarbituric acid‐reactive substances, high‐sensitivity C‐reactive protein and Hcy, whereas nitrite levels were increased. The reduction in Hcy levels in carriers of the T allele was ?20.3% compared with –9.4% in patients with the CC genotype. Importantly, before treatment, nitrite levels were significantly higher in patients with the CC genotype compared with T allele carriers, whereas after treatment these levels were similar between groups. Our findings demonstrate that obese women without comorbidities and carrying the T variant of the 677C>T polymorphism of MTHFR exhibit benefits with simvastatin treatment, mainly in terms of increased NO levels.     

Vasorelaxation induced by methyl cinnamate,the major constituent of the essential oil of Ocimum micranthum,in rat isolated aorta

The aim of the present study was to investigate the vascular effects of the E‐isomer of methyl cinnamate (E‐MC) in rat isolated aortic rings and the putative mechanisms underlying these effects. At 1–3000 μmol/L, E‐MC concentration‐dependently relaxed endothelium‐intact aortic preparations that had been precontracted with phenylephrine (PHE; 1 μmol/L), with an IC₅₀ value (geometric mean) of 877.6 μmol/L (95% confidence interval (CI) 784.1–982.2 μmol/L). These vasorelaxant effects of E‐MC remained unchanged after removal of the vascular endothelium (IC₅₀ 725.5 μmol/L; 95% CI 546.4–963.6 μmol/L) and pretreatment with 100 μmol/L N^G‐nitro‐l ‐arginine methyl ester (IC₅₀ 749.0 μmol/L; 95% CI 557.8–1005.7 μmol/L) or 10 μmol/L 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (IC₅₀ 837.2 μmol/L; 95% CI 511.4–1370.5 μmol/L). Over the concentration range 1–3000 μmol/L, E‐MC relaxed K⁺‐induced contractions in mesenteric artery preparations (IC₅₀ 314.5 μmol/L; 95% CI 141.9–697.0 μmol/L) with greater potency than in aortic preparations (IC₅₀ 1144.7 μmol/L; 95% CI 823.2–1591.9 μmol/L). In the presence of a saturating contractile concentration of K⁺ (150 mmol/L) in Ca²⁺‐containing medium combined with 3 μmol/L PHE, 1000 μmol/L E‐MC only partially reversed the contractile response. In contrast, under similar conditions, E‐MC nearly fully relaxed PHE‐induced contractions in aortic rings in a Ba²⁺‐containing medium. In preparations that were maintained under Ca²⁺‐free conditions, 600 and 1000 μmol/L E‐MC significantly reduced the contractions induced by exogenous Ca²⁺ or Ba²⁺ in KCl‐precontracted preparations, but not in PHE‐precontracted preparations (in the presence of 1 μmol/L verapamil). In addition, E‐MC (1–3000 μmol/L) concentration‐dependently relaxed the contractions induced by 2 mmol/L sodium orthovanadate. Based on these observations, E‐MC‐induced endothelium‐independent vasorelaxant effects appear to be preferentially mediated by inhibition of plasmalemmal Ca²⁺ influx through voltage‐dependent Ca²⁺ channels. However, the involvement of a myogenic mechanism in the effects of E‐MC is also possible.     

Non-invasive methods for iron overload evaluation in dysmetabolic patients

IntroductionAlthough hyperferritinemia may reflect the inflammatory status of patients with non-alcoholic fatty liver disease (NAFLD), approximately 33% of hyperferritinemia cases reflect real hepatic iron overload.AimTo evaluate a non-invasive method for assessing mild iron overload in patients with NAFLD using 3T magnetic resonance imaging (MRI) relaxometry, serum hepcidin, and the expression of ferritin subunits.MethodsThis cross-sectional study assessed patients with biopsy-proven NAFLD. MRI relaxometry was performed using a 3T scanner in all patients, and the results were compared with iron content determined by liver biopsy. Ferritin, hepcidin, and ferritin subunits were assessed and classified according to ferritin levels and to siderosis identified by liver biopsy.ResultsA total of 67 patients with NAFLD were included in the study. MRI revealed mild iron overload in all patients (sensitivity, 73.5%; specificity, 70%). For mild (grade 1) siderosis, the transverse relaxation rate (R₂*) threshold was 58.9 s^?1 and the mean value was 72.5 s^?1 (SD, 33.9), while for grades 2/3 it was 88.2 s^?1 (SD, 31.9) (p < 0.001). The hepcidin threshold for siderosis was > 30.2 ng/mL (sensitivity, 87%; specificity, 82%). Ferritin H and ferritin L subunits were expressed similarly in patients with NAFLD, regardless of siderosis. There were no significant differences in laboratory test results between the groups, including glucose parameters and liver function tests.ConclusionsMRI relaxometry and serum hepcidin accurately assessed mild iron overload in patients with dysmetabolic iron overload syndrome.