Micro-pharmacokinetics of lidocaine and bupivacaine transfer across a myelinated nerve fiber.

BACKGROUND: The aim of the present study was to predict the time to onset and duration of action of two local anesthetics (lidocaine and bupivacaine) based on experimental dimensions of a typical nerve and experimental octanol/water partition coefficients. METHODS: We began our compilation of experimental data with a numerical solution of the Smoluchowski equation for the transfer of lidocaine and bupivacaine across the axon membrane in the region of the node of Ranvier (axolemma) and across the Schwann cell. The difference between the aqueous and lipid environments of the neuron was simulated by including the coordinate-dependent chemical potential. In the second step, the permeation rates calculated using the diffusion equation were used to solve a system of four ordinary differential equations. This approach allowed us to simulate the cellular environment for a longer time and to compare our model with pharmacokinetic properties (time to onset and duration of action) of local anesthetics from the literature. The behavior of local anesthetics under physiological conditions and in case of local acidosis was also simulated. RESULTS: We demonstrated that local anesthetics cross the axolemma in a time span of less than 1 µs. The time to onset of action, controlled by diffusion from the epineurium to an axon with a typical distance of 500 µm, was 167 s and 186 s for lidocaine and bupivacaine, respectively. The calculated half-life, which is a measure of the duration of action, was 41 min and 328 min for lidocaine and bupivacaine, respectively. CONCLUSIONS: Duration of action is controlled by the storage capacity of lipophilic compartments around the axon, which is higher for bupivacaine but lower in local acidosis. For the latter case, the literature, including textbooks, provides a misinterpretation, namely that protonated species cannot penetrate the membrane.

How Azide Ion/Hydrazoic Acid Passes Through Biological Membranes: An Experimental and Computational Study.

Hydrazoic acid (HN3) and its deprotonated form azide ion (N3-) (AHA) are toxic because they inhibit the cytochrome c oxidase complex IV (CoX IV) embedded in the inner mitochondrial membrane that forms part of the enzyme complexes involved in cellular respiration. Critical to its toxicity is the inhibition of CoX IV in the central nervous system and cardiovascular system. Hydrazoic acid is an ionizable species and its affinity for membranes, and the associated permeabilities, depend on the pH values of aqueous media on both sides of the membranes. In this article, we address the permeability of AHA through the biological membrane. In order to understand the affinity of the membrane for the neutral and ionized form of azide, we measured the octanol/water partition coefficients at pH values of 2.0 and 8.0, which are 2.01 and 0.00034, respectively. Using a Parallel Artificial Membrane Permeability Assay (PAMPA) experiment, we measured the effective permeability through the membrane, which is logPe - 4.97 and - 5.26 for pH values of 7.4 and pH 8.0, respectively. Experimental permeability was used to validate theoretical permeability, which was estimated by numerically solving a Smoluchowski equation for AHA diffusion through the membrane. We demonstrated that the rate of permeation through the cell membrane of 8.46·104 s-1 is much higher than the rate of the chemical step of CoX IV inhibition by azide of 200 s-1. The results of this study show that transport through the membrane does not represent the rate-limiting step and therefore does not control the rate of CoX IV inhibition in the mitochondria. However, the observed dynamics of azide poisoning is controlled by circulatory transport that takes place on a time scale of minutes.

Cervical Intraepithelial Neoplasia Grade 3 in a HPV-Vaccinated Patient: A Case Report.

Persistent infection with human papillomavirus (HPV) causes almost all cervical precancerous lesions and cancers. Bivalent, quadrivalent, and nonavalent HPV vaccines effectively prevent high-grade cervical intraepithelial neoplasia (CIN3). The effectiveness of HPV vaccination against CIN3 is 97-100% in HPV-naïve populations and 44-61% in the overall population. Although HPV vaccination has substantially reduced the incidence of cervical cancers, several cases of precancerous cervical lesions in HPV-vaccinated patients have been reported. We report the clinical case of a 19-year-old woman whose first Pap smear was diagnosed as a high-grade squamous intraepithelial lesion (HSIL) after quadrivalent HPV vaccination. Colposcopy and cervical biopsy were performed, revealing HSIL/CIN3. Our multidisciplinary team decided to take a conservative approach with follow-up visits with cervical biopsies of this young patient. After six months, spontaneous regression of high-grade cervical dysplasia was observed. Although HPV immunization has shown to be extremely effective in preventing a high proportion of cervical precancerous lesions and cervical cancers, HPV vaccines do not protect against all oncogenic high-risk HPV genotypes. Consequently, healthcare providers must encourage HPV-vaccinated women to still regularly attend national cervical screening programs.

The Reliability and Medical Students' Appreciation of Certainty-Based Marking.

Certainty-Based Marking (CBM) involves asking students not only the answer to an objective question, but also how certain they are that their answer is correct. In a mixed method design employing an embedded approach with a quasi-experimental design, we have examined the use of CBM during a 5-week Gynaecology and Obstetrics course. The study was conducted as a non-mandatory revision exam with two additional questionnaires on Moodle. Majority of students perceive CBM as fair (78%) and useful (94%). Most students would immediately want CBM to be used for revision exams, but more practice would be needed for CBM to be used in graded exams. The lowest self-evaluation of knowledge was mostly seen by worst (less than 70% Accuracy) and best achievers (more than 90% Accuracy); the worst achievers probably have knowledge gaps, and the best achievers probably correctly guessed at least one question. Our findings conclude that CBM does not discriminate any learner type (p = 0.932) and does not change the general distribution of the exam scores, since there is no significant differences between Certainty-Based Score (M = 80.4%, SD = 10.4%) and Accuracy (M = 79.8%, SD = 11.1%); t(176) = 0.8327, p = 0.4061. These findings are widely applicable, as learner type study models are used extensively in education. In the future, larger samples should be studied and the implementation of CBM on question types other than MCQ should be investigated.

Overview of Immune Checkpoint Inhibitors in Gynecological Cancer Treatment.

In the last ten years, clinical oncology has been revolutionized by the introduction of oncological immunotherapy, mainly in the form of immune checkpoint inhibitors (ICIs) that transformed the standard of care of several advanced solid malignancies. Using ICIs for advanced gynecological cancers has yielded good results, especially for endometrial cancer. In ovarian or cervical cancer, combining ICIs with other established agents has shown some promise. Concurrently with the clinical development of ICIs, biomarkers that predict responses to such therapy have been discovered and used in clinical trials. The translation of these biomarkers to clinical practice was somewhat hampered by lacking assay standardization and non-comprehensive reporting of biomarker status in trials often performed on a small number of gynecological cancer patients. We can expect increased use of ICIs combined with other agents in gynecological cancer in the near future. This will create a need for reliable response prediction tools, which we believe will be based on biomarker, clinical, and tumor characteristics. In this article, we review the basic biology of ICIs and response prediction biomarkers, as well as the latest clinical trials that focus on subgroup effectiveness based on biomarker status in gynecological cancer patients.

Is tissue augmentation a reality in biosurgery? An experimental study of endothelial cell invasion into tissue filler.

New therapeutic approaches for wound treatment are evolving. Non healing wounds in oncology and after trauma may be cured by a novel technique of tissue augmentation with soft tissue fillers. The principle resides in filling the wound with collagen filler in order to seal the defect and promote healing. Successful angiogenesis forms the basis of tissue filler survival and determines the outcome of the healing process. During this study, basic data about endothelial cell invasion into collagen-made substratum was collected that could be used for neoangiogenesis studies in tissue augmentation techniques for large wound defect treatment. In the in vitro assay, the human umbilical vein endothelial cells (HUVEC) grow into a three-dimensional framework of collagenous tissue fillers, forming the basic step for angiogenesis. After heparins were used as chemotactic agents, a typical bell-shaped relationship between chemotaxis and agent concentrations was found. Significant cell infiltration was present in the assays with chemotactic agents. These observations support the potential for tissue augmentation with soft tissue fillers that could be used in acute and chronic non healing traumatic and oncology wounds after extensive surgical resections and radiotherapy.

An unusual case of high cervical spinal cord injury.

Isolated spinal cord injuries can rarely be found in patients with no traumatic radiological abnormalities of the spine. Stenoses of the medullary canal and degeneration of cervical spine are the predisposing factors. A case report of a 68-year-old patient is described, who developed quadriplegia with cardiac arrest due to isolated cervical spinal cord injury while jumping on a trampoline. Compressions of the spinal cord with intramedullary and epidural haemorrhage between vertebrae C3 and C6 were observed with no traumatic radiological abnormalities of the spine skeleton.

Percutaneous versus open repair of the ruptured Achilles tendon: a comparative study.

BACKGROUND: Controversy regarding the optimal treatment of the fresh total Achilles tendon rupture remains. PURPOSE: To compare the results of percutaneous and open Achilles tendon repair. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: The results of 132 consecutive patients with acute complete Achilles tendon rupture who were operated on exclusively with modified percutaneous repair under local anesthesia from 1991 to 1997 and followed up for at least 2 years were compared to the results of 105 consecutive patients who were operated on exclusively with open repair under general or spinal anesthesia in the same period. RESULTS: There were significantly fewer major complications in the group of percutaneous repairs in comparison with the group of open repairs (4.5% vs 12.4%; P = .03), particularly necrosis (0% vs 5.6%; P = .019), and a lower total number of complications (9.7% vs 21%; P = .013). There were slightly more reruptures (3.7% vs 2.8%; P = .680) and sural nerve disturbances (4.5% vs 2.8%; P = .487) in the group of percutaneous repairs, with no statistically significant difference. Functional assessment using the American Orthopaedic Foot and Ankle Society scale and the Holz score showed no statistically significant difference. CONCLUSION: The results of the study support the choice of (modified) percutaneous suturing under local anesthesia as the method that brings comparable functional results to open repair, with a significantly lower rate of complications.

Percutaneous suturing of the ruptured Achilles tendon under local anesthesia.

A prospective study of modified percutaneous Achilles tendon repair performed from 1991 to 1997 under local anesthesia with a minimum 2-year follow-up is presented. There were 134 procedures in 124 men and 8 women (mean age, 37 years) treated within 7 days after acute total rupture. Postoperative care consisted of wearing a cast or soft-cast immobilization for 6 weeks. The procedure was well tolerated in all patients. There was 1 (0.7%) complete and 4 (3%) partial reruptures. Six patients (4.5%) developed transient sural neuritis that spontaneously resolved in 3 to 10 months. One case of deep venous thrombosis was successfully treated. There were no cases of increased postoperative dorsiflexion, deep infection, or necrosis. Eighteen patients (14%) had a slightly decreased range of ankle motion; 129 (98%) patients, including all high-caliber athletes, resumed all their previous activities, 22 of them (17%) with some minor complaints. The mean American Orthopedic Foot and Ankle Society's ankle-hindfoot score was 96 points. The proposed method offers a reasonable treatment option for acute total Achilles tendon ruptures, with a low number of complications and a low risk of sural nerve injury. The rerupture rate and return to preinjury activities is comparable to open procedures.