Electrochemistry of Anticonvulsants: Electron Transfer as a Possible Mode of Action

Reduction potentials were determined for various anticonvulsants, including progabide, SL 75.102, CGS 9896, pyridazines, zonisamide, 1,2,3-triazoles, and copper complexes. The values generally were in the range of about -0.1 to -0.6 V for the protonated drugs and the metal complexes. Reduction potentials provide information on the feasibility of electron transfer (ET) in vivo. If the value is relatively positive (greater than about -0.6 V), the agent can act catalytically as an electron acceptor from an appropriate cellular donor. A concomitant favorable influence on abnormal neuronal processes associated with epilepsy could occur. We describe ET as a possible mode of action of anticonvulsants as well as some antiepileptic agents with no electrochemical data based on this hypothetical ET approach.     

Transient pulmonary perfusion scintigraphic abnormalities in pulmonary air embolism

A critically ill man suffered a respiratory arrest due to pulmonary air embolism after the exchange of central venous catheters over a guidewire. A pulmonary perfusion lung scan performed 90 min later demonstrated extensive perfusion defects which were interpreted as "high probability" for PTE. Pulmonary angiography 4.5 h later was normal. A second perfusion lung scan performed 24 h after the respiratory arrest was normal. Pulmonary air embolism can produce segmental (and larger) perfusion defects which may be indistinguishable from those caused by PTE. The rapid (24 h) resolution of the perfusion defects may help differentiate the two disorders.     

Dopaminergic neuronal responses to a non-amphetamine CNS stimulant

Summary The present study compares the effects of d-amphetamine (d-AMP) and the potent non-amphetamine CNS stimulant, amfonelic acid (AFA), on the firing rate of single midbrain dopaminergic (DA) neurons and on neostriatal DA metabolism (dihydroxyphenylacetic acid—DOPAC). The results indicate that AFA, like d-AMP, reduces the firing rate of DA neurons, although unlike d-AMP, AFA does not cause a decrease in neostriatal DOPAC content and, in fact, enhances that produced by haloperidol (HALO). The AFA-induced decrease in firing rate, like d-AMP, is reversed by the DA receptor blocker HALO, but again unlike d-AMP, the decrease in firing rate is not prevented by catecholamine synthesis inhibition with-methyl-para-tyrosine. Thus, both amphetamine and amfonelic acid have identical electrophysiological effects on DA neurons but act by different mechanisms.     

Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells

Detailed studies of tumor cell-associated procoagulants and fibrinolytic factors have implied that local thrombin generation and fibrin deposition and dissolution may be important in tumor growth and dissemination. To directly determine whether fibrin(ogen) or plasmin(ogen) are determinants of the metastatic potential of circulating tumor cells, this study examined the impact of genetic deficits in each of these key hemostatic factors on the hematogenous pulmonary metastasis of 2 established murine tumors, Lewis lung carcinoma and the B16-BL6 melanoma. In both tumor models, fibrinogen deficiency strongly diminished, but did not prevent, the development of lung metastasis. The quantitative reduction in metastasis in fibrinogen-deficient mice was not due to any appreciable difference in tumor stroma formation or tumor growth. Rather, tumor cell fate studies indicated an important role for fibrin(ogen) in sustained adhesion and survival of tumor cells within the lung. The specific thrombin inhibitor, hirudin, further diminished the metastatic potential of circulating tumor cells in fibrinogen-deficient mice, although the inhibitor had no apparent effect on tumor cell proliferation in vitro. The absence of plasminogen and plasmin-mediated fibrinolysis had no significant impact on hematogenous metastasis. The authors concluded that fibrin(ogen) is a critical determinant of the metastatic potential of circulating tumor cells. Furthermore, thrombin appears to facilitate tumor dissemination through at least one fibrin(ogen)-independent mechanism. These findings suggest that therapeutic strategies focusing on multiple distinct hemostatic factors might be beneficial in the containment of tumor metastasis.     

Evaluation of safety and efficacy outcomes of direct oral anticoagulants versus warfarin in normal and extreme body weights for the treatment of atrial fibrillation or venous thromboembolism

Journal of Thrombosis and Thrombolysis - Despite evolving evidence, the use of direct oral anticoagulants (DOACs) in patients with extremes of body weight remains controversial. This study aimed to...     

Bilateral Improvements in Lower Extremity Function After Unilateral Balance Training in Individuals With Chronic Ankle Instability

Context:

Bilateral improvements in postural control have been reported among individuals with acute lateral ankle sprains and individuals with chronic ankle instability (CAI) when only the unstable ankle is rehabilitated. We do not know if training the stable ankle will improve function on the unstable side.

Objective:

To explore the effects of a unilateral balance-training program on bilateral lower extremity balance and function in individuals with CAI when only the stable limb is trained.

Design:

Cohort study.

Setting:

University clinical research laboratory.

Patients or Other Participants:

A total of 34 volunteers (8 men, 26 women; age = 24.32 ± 4.95 years, height = 167.01 ± 9.45 cm, mass = 77.54 ± 23.76 kg) with CAI were assigned to the rehabilitation (n = 17) or control (n = 17) group. Of those, 27 (13 rehabilitation group, 14 control group) completed the study.

Intervention(s):

Balance training twice weekly for 4 weeks.

Main Outcome Measure(s):

Foot and Ankle Disability Index (FADI), FADI Sport (FADI-S), Star Excursion Balance Test, and Balance Error Scoring System.

Results:

The rehabilitation and control groups differed in changes in FADI-S and Star Excursion Balance Test scores over time. Only the rehabilitation group improved in the FADI-S and in the posteromedial and anterior reaches of the Star Excursion Balance Test. Both groups demonstrated improvements in posterolateral reach; however, the rehabilitation group demonstrated greater improvement than the control group. When the groups were combined, participants reported improvements in FADI and FADI-S scores for the unstable ankle but not the stable ankle.

Conclusions:

Our data suggest training the stable ankle may result in improvements in balance and lower extremity function in the unstable ankle. This further supports the existence of a centrally mediated mechanism in the development of postural-control deficits after injury, as well as improved postural control after rehabilitation.Key Words: overflow, crossover training, rehabilitation

Key Points

• The rehabilitation group performed better over time on the Foot and Ankle Disability Index Sport and the Star Excursion Balance Test (SEBT) in the anterior, posteromedial, and posterolateral directions, but this was not dependent on ankle.
• Training the stable ankle may provide therapeutic benefit to the unstable ankle.
• Performance on the Balance Error Scoring System did not reflect a therapeutic benefit of the neuromuscular-control training program, but the result should be interpreted with caution.
• Clinicians should consider incorporating rehabilitation of the stable ankle in the overall plan for patients who may not be ready to initiate aspects of rehabilitation on the unstable ankle.

Lateral ankle sprain (LAS) is one of the most common injuries that athletes and recreationally active individuals sustain. Researchers have estimated that approximately 23 000 ankle sprains occur each day in the United States, equating to 1 sprain per 10 000 people.¹ As many as 33% to 42% of these injuries result in chronic ankle instability (CAI).^2,3 In the literature, CAI has been defined as the tendency of the ankle to “give way” during normal activity and can occur in the absence of mechanical instability.^4–6 One explanation for this tendency is that damage to the peripheral mechanoreceptors that provide proprioceptive input results in altered efferent modulation. Together, the changes in afferent input and efferent output are recognized as altered neuromuscular control (NMC). When specifically considering the role of NMC in facilitating joint stability, NMC has been defined as “the unconscious activation of dynamic restraints occurring in preparation for and in response to joint motion and loading.”⁷ Ultimately, altered NMC is thought to result in functional ankle instability.^3,4,8 Even after the injury has healed, mechanoreceptors may not function properly, resulting in NMC deficits that can lead to CAI.^3,8In addition to damage at the level of the receptors, changes in central nervous system processing and integration also may contribute to CAI.^9,10 Evidence has suggested that when an injury occurs, this central mechanism for NMC is disrupted.^9–12 Reports of bilateral postural-control deficits after acute LAS have provided further evidence that central pathways are affected by injury.^9,10,13 In addition, researchers^10,14–16 have found bilateral improvements in NMC and postural stability after rehabilitation of acute LAS and CAI. This suggests that NMC is not controlled solely by peripheral mechanoreceptors and that deficits after LAS may be partly due to adaptations in the central pathways. Whereas investigators^10,14–16 have shown a carryover effect after training the involved lower extremity, no one has examined whether training the stable ankle results in improvements to the unstable ankle.Given these reports of bilateral deficits after unilateral injury and improvements in NMC and postural stability in the stable ankle after training only the unstable ankle, it is conceivable that training the stable ankle in individuals with CAI would result in improvements of the unstable ankle. This is meaningful because clinicians may be able to begin neuromuscular retraining earlier and the athlete may be able to return to sport participation better prepared without increasing the time missed. After an acute LAS, many athletes return to sport participation within 15 days¹⁷ despite postural-control deficits being measured up to 21 days after injury⁹ and many reporting pain and functional deficits 6 months later.¹⁷ Researchers¹⁸ also have recommended that NMC training should not begin immediately because of pain and weight-bearing restrictions. Therefore, the amount of time spent restoring NMC before return to sport participation is minimal, likely resulting in athletes returning with residual dysfunction and increased risk for reinjury. By beginning NMC retraining sooner, it is plausible that athletes may return to sport participation with less dysfunction and more prepared for the functional demands of sport. Therefore, the purpose of our study was to explore the effects of a 4-week, unilateral balance-training program on bilateral lower extremity balance and function in individuals with CAI. Our hypothesis was that bilateral improvements would occur after training of the stable ankle.