Surgical Operative Time Increases the Risk of Deep Venous Thrombosis and Pulmonary Embolism in Robotic Prostatectomy

Background and Objectives:

To evaluate the effect of operative time on the risk of symptomatic venous thromboembolic events (VTEs) in patients undergoing robot-assisted radical prostatectomy (RARP).

Methods:

We reviewed the records of all patients at our institution who underwent RARP by a single surgeon from January 2007 until April 2011. Clinical and pathologic information and VTE incidence were recorded for each patient and analyzed by use of logistic regression to evaluate for association with VTE risk. All patients had mechanical prophylaxis, and beginning in February 2008, a single dose of unfractionated heparin, 5000 U, was administered before surgery.

Results:

A total of 549 consecutive patients were identified, with a median follow-up period of 8 months. During the initial 30 days postoperatively, 10 patients (1.8%) had a VTE (deep venous thrombosis in 7 and pulmonary embolism in 3). The median operative time was 177 minutes (range, 121–360 minutes). An increase in operative time of 30 or 60 minutes was associated with 1.6 and 2.8 times increased VTE risks. A 5-point increase in body mass index and need for blood transfusion were also associated with increased risk of VTEs (odds ratios of 2.0 and 11.8, respectively). Heparin prophylaxis was not associated with a significant VTE risk reduction but also was not associated with a significant increase in estimated blood loss (P = .23) or transfusion rate (P = .37).

Conclusion:

A prolonged operative time increases the risk of symptomatic VTEs after RARP. Future studies are needed to evaluate the best VTE prophylactic approach in patients at risk.     

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.     

Unravelling mitochondrial pathways to Parkinson's disease

Mitochondria are essential for cellular function due to their role in ATP production, calcium homeostasis and apoptotic signalling. Neurons are heavily reliant on mitochondrial integrity for their complex signalling, plasticity and excitability properties, and to ensure cell survival over decades. The maintenance of a pool of healthy mitochondria that can meet the bioenergetic demands of a neuron, is therefore of critical importance; this is achieved by maintaining a careful balance between mitochondrial biogenesis, mitochondrial trafficking, mitochondrial dynamics and mitophagy. The molecular mechanisms that underlie these processes are gradually being elucidated. It is widely recognized that mitochondrial dysfunction occurs in many neurodegenerative diseases, including Parkinson''s disease. Mitochondrial dysfunction in the form of reduced bioenergetic capacity, increased oxidative stress and reduced resistance to stress, is observed in several Parkinson''s disease models. However, identification of the recessive genes implicated in Parkinson''s disease has revealed a common pathway involving mitochondrial dynamics, transport, turnover and mitophagy. This body of work has led to the hypothesis that the homeostatic mechanisms that ensure a healthy mitochondrial pool are key to neuronal function and integrity. In this paradigm, impaired mitochondrial dynamics and clearance result in the accumulation of damaged and dysfunctional mitochondria, which may directly induce neuronal dysfunction and death. In this review, we consider the mechanisms by which mitochondrial dysfunction may lead to neurodegeneration. In particular, we focus on the mechanisms that underlie mitochondrial homeostasis, and discuss their importance in neuronal integrity and neurodegeneration in Parkinson''s disease.

LINKED ARTICLES

This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8     

Metformin and male reproduction: effects on Sertoli cell metabolism

Background and Purpose

Metformin is commonly used to treat type 2 diabetes (T2D). While new clinical applications have been ascribed to metformin, including treatment of anovulatory infertility, its effects on male reproduction have not been investigated. The Sertoli cell (SC) is crucial for germ cell development, exerting metabolic control of spermatogenesis, therefore, we investigated the effects of metformin on SC metabolism.

Experimental Approach

Rat SCs were cultured in the absence and presence of metformin (5, 50 and 500 μM). mRNA and protein levels of glucose transporters (GLUT1 and GLUT3), phosphofructokinase 1 (PFK 1), lactate dehydrogenase (LDH) and monocarboxylate transporter 4 (MCT4) were determined by quantitative PCR and Western blot respectively. LDH activity was assessed and metabolite production/consumption determined by ¹H-NMR.

Key Results

Metformin (50 μM) decreased mRNA and protein levels of GLUT1, GLUT3, MCT4 and PFK 1 but did not affect LDH mRNA or protein levels. However, although glucose consumption was maintained in metformin-treated cells, LDH activity, lactate and alanine production were increased, indicating an enhanced glycolytic flux. No metabolic cytotoxicity was detected in SCs exposed to supra-pharmacological concentration of metformin.

Conclusions and Implications

Our results indicate that metformin: (i) decreases mRNA and protein levels of glycolysis-related transporters in SCs but increases their activity; and (ii) stimulates alanine production, which induces antioxidant activity and maintains the NADH/NAD⁺ equilibrium. The increased lactate in metformin-treated SCs provides nutritional support and has an anti-apoptotic effect in developing germ cells. Thus, metformin can be considered as a suitable antidiabetic drug for male patients of reproductive age with T2D.