Impact of VKORC1, CYP2C9, and CYP4F2 Polymorphisms on Optimal Warfarin Dose: Does Ethnicity Matters?

BACKGROUND: Conventional anticoagulation with warfarin remains the cornerstone strategy for numerous preventive strategies. It is established that Asian patients require lower warfarin doses than Caucasians potentially attributing to the genetic polymorphism (GP) differences. AREAS OF UNCERTAINTY: The impact of GP on optimal warfarin dose (OWD) in Koreans is unclear when compared with other ethnicities. It is also not well established whether GP linked to OWD in Korean patients to the similar extend as in Chinese, Japanese, and Caucasians. DATA SOURCES: Single-center prospective observational study in Koreans, matched with historic cohorts of other ethnicities. THERAPEUTIC ADVANCES: Clinical characteristics, concomitant medications, OWD, international normalized ratio, and VKORC1, CYP2C9, and CYP4F2 GPs were assessed in consecutive Korean patients. The OWD was defined when patient's international normalized ratio was within target range for at least 3 consecutive times separated by 1 week. We included 133 (mean age 62.6 ± 12.1 years, 49% males) warfarin-treated patients of Korean descend. The mean OWD was 3.30 ± 1.34 (range: 1-9) mg/d. Homozygous wild-type patients required lower OWD (3.1 ± 1.1 mg/d vs. 4.7 ± 1.8 mg/d, P < 0.001) for VKORC1 and higher OWD for both CYP2C9 (3.4 ± 1.3 mg/d vs. 2.3 ± 1.1 mg/d, P = 0.002) and CYP4F2 (3.0 ± 1.2 mg/d vs. 3.4 ± 1.3 mg/d vs. 4.0 ± 1.7 mg/d, P = 0.033) than those carrying heterozygote genes. CONCLUSIONS: Korean patients exhibit different VKORC1, CYP2C9, and CYP4F2 profiles impacting lower OWD in Eastern Asians than required in Caucasians. Universal international OWD guidelines may consider patient ethnicity as a confounder; however, this hypothesis needs further clarification.

Provision of emergency hyperbaric oxygen treatment for a patient during the COVID-19 pandemic.

The experience of managing a critically ill severe carbon monoxide poisoning patient suspected of possibly also suffering COVID-19 and requiring emergency hyperbaric oxygen treatment is described. Strategies used to minimise infection risk, modifications to practice and lessons learnt are described. All aerosol generating procedures such as endotracheal tube manipulation and suctioning should be undertaken in a negative pressure room. In the absence of in-chamber aerosol generating procedures, an intubated patient presents less risk than that of a non-intubated, symptomatically coughing patient. Strict infection control practices, contact precautions, hospital workflows and teamwork are required for the successful HBOT administration to an intubated COVID-19 suspect patient.

Robotic single-site surgery in benign gynecologic diseases: Experiences and learning curve based on 626 robotic cases at a single institute.

AIM: The purpose of this study was to report on 626 cases of successful robotic single-site (RSS) surgeries to address various types of gynecologic disease and to evaluate the outcomes and learning curve inherent to RSS surgery in the gynecology field. METHODS: A total of 626 cases of RSS surgeries were performed by 3 gynecologic surgeons at Ewha Womans University Medical Center, Robot Surgery Center from November 2014 to January 2018 were collected retrospectively. All of the patients' charts were reviewed, and the clinical characteristics and surgical variables were analyzed. RESULTS: Among the total of 626 cases, there were 220 cases of RSS myomectomy (RSSM), 182 cases of RSS hysterectomy (RSSH), 195 of RSS adnexectomy, 24 of RSS sacrocolpopexy (RSS SCP) and 5 were classified as other RSS surgeries. The patient's mean age was 38.98 ± 10.07 years. There was 3.99 ± 2.15 min of mean docking time and 117.78 ± 51.18 min of mean operating time. The surgical variables were analyzed annually. The total operating time was seen to decrease significantly according to each period. The docking time declined significantly and gradually after 1 year. We also analyzed each of the surgical types by time. The operating time of RSSH, RSSM, RSS adnexectomy and RSS SCP fell over time. The tendency found was for operating time to decline sharply following the first 10 cases. When we analyzed the data at annual intervals, the operating time was most significantly less and stable following the first year. There were a few intraoperative or perioperative complications in 16 cases (2.6%). CONCLUSION: Robotic single-site surgery is a feasible and safe procedure for treating various kinds of gynecologic diseases. The learning curve was approximately 10 cases of RSS surgery in gynecologic disease, having a greater amount of experience at performing RSS surgery was revealed to be key to achieving better surgical outcomes.

Meissner corpuscles and their spatially intermingled afferents underlie gentle touch perception.

Meissner corpuscles are mechanosensory end organs that densely occupy mammalian glabrous skin. We generated mice that selectively lacked Meissner corpuscles and found them to be deficient in both perceiving the gentlest detectable forces acting on glabrous skin and fine sensorimotor control. We found that Meissner corpuscles are innervated by two mechanoreceptor subtypes that exhibit distinct responses to tactile stimuli. The anatomical receptive fields of these two mechanoreceptor subtypes homotypically tile glabrous skin in a manner that is offset with respect to one another. Electron microscopic analysis of the two Meissner afferents within the corpuscle supports a model in which the extent of lamellar cell wrappings of mechanoreceptor endings determines their force sensitivity thresholds and kinetic properties.

Endothelial-specific Crif1 deletion induces BBB maturation and disruption via the alteration of actin dynamics by impaired mitochondrial respiration.

Cerebral endothelial cells (ECs) require junctional proteins to maintain blood-brain barrier (BBB) integrity, restricting toxic substances and controlling peripheral immune cells with a higher concentration of mitochondria than ECs of peripheral capillaries. The mechanism underlying BBB disruption by defective mitochondrial oxidative phosphorylation (OxPhos) is unclear in a mitochondria-related gene-targeted animal model. To assess the role of EC mitochondrial OxPhos function in the maintenance of the BBB, we developed an EC-specific CR6-interactin factor1 (Crif1) deletion mouse. We clearly observed defects in motor behavior, uncompacted myelin and leukocyte infiltration caused by BBB maturation and disruption in this mice. Furthermore, we investigated the alteration in the actin cytoskeleton, which interacts with junctional proteins to support BBB integrity. Loss of Crif1 led to reorganization of the actin cytoskeleton and a decrease in tight junction-associated protein expression through an ATP production defect in vitro and in vivo. Based on these results, we suggest that mitochondrial OxPhos is important for the maturation and maintenance of BBB integrity by supplying ATP to cerebral ECs.

Total FDG lesion number on PET/CT predicts survival of esophageal carcinoma patients with recurrence following curative surgery.

BACKGROUND: Total lesion number is a prognostic determinant in recurrent esophageal cancer, but this requires multiple tests. Here, we investigated the prognostic value of total FDG lesion number obtained from a single PET/CT study. METHODS: Subjects were 153 esophageal squamous cell carcinoma patients with loco-regional or distant recurrence following curative surgery. FDG PET/CT performed within 30 days was inspected for abnormal FDG uptake lesions using a SUVmax of 3.0 as threshold for significance. Prognostic associations were assessed by Cox proportional hazards regression and Kaplan-Meier analysis. RESULTS: PET/CT showed significant local FDG lesions in 49.0%, regional lesions in 78.4%, and distant lesions in 44.4% of patients. Among 73 patients with loco-regional recurrence, 54 had 0-3 and 19 had ≥4 FDG lesions. Among 80 patients with distant recurrence, 31 had 0-3 and 49 had ≥4 FDG lesions. During a median follow-up of 11.8 months, 99 deaths occurred. Univariate variables associated with poor survival included ≥4 FDG lesions and no treatment for loco-regional recurrence and no treatment for distant recurrence. Kaplan Meier analysis showed worse survival for ≥4 than 0-3 FDG lesions in patients with loco-regional recurrence (15.6 vs. 32.1 months; P=0.009), but not in those with distant recurrence. Significant independent predictors of poor survival were ≥4 FDG lesions and no treatment for loco-regional recurrence and no treatment for distant recurrence. CONCLUSIONS: Total FDG lesion number assessed by PET/CT is a significant independent prognostic factor in esophageal cancer patients with loco-regional recurrence following curative surgery.

Corrigendum: Insight Into the Interaction Between RNA Polymerase and VPg for Murine Norovirus Replication.

[This corrects the article DOI: 10.3389/fmicb.2018.01466.].

Insight Into the Interaction Between RNA Polymerase and VPg for Murine Norovirus Replication.

Norovirus (NoV) is a leading cause of epidemic acute non-bacterial gastroenteritis, and replicates through virion protein genome-linked (VPg)-primed or de novo RNA synthesis by RNA-dependent RNA polymerase (RdRp). VPg is a multifunctional protein that plays crucial roles in viral protein translation and genome replication. However, the interaction between the RdRp and this multifunctional VPg in NoV replication has been unknown. In this study, VPg derived from murine NoV (MNV) was found to mediate the formation of higher-order multimers or tubular fibrils of MNV RdRp, which led to significantly enhanced polymerase activity in vitro. The replication of MNV mutants containing a VPg-binding defective RdRp, based on the crystal structure of an RdRp-VPg(1-73) complex, was completely blocked in a cell culture system. Our data suggest that the interaction between RdRp and VPg plays a crucial role in the multimerization-mediated RdRp activity in vivo and consequently in MNV replication, which can provide a new target of therapeutic intervention for NoV outbreaks.

Thrombotic Thrombocytopenic Purpura Associated With Pegylated Interferon Alfa-2a Use in a Patient With Polycythemia Vera.

Pegylated interferon alfa-2a (pegIFNa) is being increasingly used for treatment of myeloproliferative neoplasms; however, its side effects, including autoimmune complications, are not unusual. We report on a 47-year-old woman with polycythemia vera (PV) treated with pegIFNa and in complete hematologic remission who developed thrombotic thrombocytopenic purpura (TTP). To our knowledge, thrombotic microangiopathy has been reported as a side effect of interferon (IFN) use in patients with hepatitis and chronic myeloid leukemia, but not in those with PV. Our patient had a low ADAMTS13 level due to an inhibitor, which normalized after withholding pegIFNa and initiating treatment for TTP with therapeutic plasma exchange and corticosteroids. She experienced refractory TTP, necessitating treatment with rituximab and splenectomy. Postsplenectomy, she developed a high platelet count, warranting the need to restart treatment for PV. However, JAK2V617F allelic burden by real-time PCR was 0.7%, indicating that the increased platelet count was likely secondary to splenectomy. Therefore, we elected to monitor her counts and JAK2V617F allelic burden closely. With this case report, we hope to alert treating physicians that TTP should be considered as a complication of pegIFNa therapy in PV and that prompt discontinuation of the drug with necessary treatment should be instituted to prevent fatal complications.

Incidental 99mTc MDP uptake in the intestines and intravenous CT contrast.

AIM: We evaluated the association between intestinal visualization on bone scintigraphy and IV CT contrast in patients with breast cancer. PATIENTS, METHODS: 452 patients with breast cancer underwent a 99mTc methylene diphosphonate (MDP) bone scan for surveillance of bone metastasis. Presence, site and intensity of intestinal uptake were visually assessed. For patients with intestinal visualization, medical records were reviewed to identify the alleged potential causes. When IV CT contrast was administrated on the same day as bone scan, the time between IV CT contrast injection, 99mTc MDP administration and bone scan was assessed. RESULTS: Intestinal 99mTc MDP uptake was observed in 44 of the 452 patients (9.7%). Bone scans showed no thyroid or gastric uptake that suggested free pertechnetate. There were no patients with documented causes of intestinal uptake except for one patient with vesicoenteric fistula. Of the 452 patients, 149 (33.0%) underwent IV contrast-enhanced CT on the same day as bone scan. Forty of the 44 patients (90.9%) with intestinal uptake on bone scan underwent IV contrast-enhanced CT on the same day, whereas 109 of 408 (26.7%) patients without intestinal uptake on bone scintigraphy underwent IV contrast-enhanced CT on the same day (p < 0.001). The patients who underwent IV contrast injection between Tc-99m MDP administration and acquisition of bone scans had significantly more frequent intestinal uptake than patients who underwent IV contrast injection either before 99mTc MDP administration or after bone scanning (42.4% vs. 1.8%, p < 0.001). CONCLUSIONS: IV CT contrast injection administered on the same day as bone scintigraphy is significantly associated with 99mTc MDP uptake in the intestines among patients with breast cancer.

Electromechanical modulation of catabolic and anabolic pathways in chronically inactive, but neurally intact, muscles.

The extent and mechanisms by which neural input regulates skeletal muscle mass remain largely unknown. Adult spinal cord isolated (SI) rats were implanted unilaterally with a microstimulator, whereas the contralateral limb served as SI control (SI-C). A 100-HZ, 1-s stimulus was delivered every 30 s for 5 min, followed by a 5-min rest. This was repeated six times consecutively (SI-Stim1) or with a 9-h interval after the third bout (SI-Stim2) for 30 days (1 min of daily activity). SI-Stim1 and SI-Stim2 paradigms attenuated plantaris atrophy by 20% and 38%, respectively, whereas only SI-Stim2 blunted soleus atrophy (24%) relative to SI-C. Muscle mass changes occurred independent of the IGF-1/PI3K/Akt pathway. No relationships between SI or electromechanical stimulation and expression of several atrophy markers were observed. These data suggest that regulatory mechanisms for maintaining muscle mass previously shown in acute states of atrophy differ substantially from those observed in chronic states.

Gene expression during inactivity-induced muscle atrophy: effects of brief bouts of a forceful contraction countermeasure.

Anabolic and catabolic markers of muscle protein metabolism were examined in inactivity-induced atrophying muscles with and without daily short-duration, high-resistance isometric contractions. Inactivity was achieved via spinal cord isolation (SI), which results in near inactivity of the hindlimb musculature without compromising the motoneuron-muscle connectivity. Adult rats were assigned to a control (Con) or SI group in which one limb was stimulated (SI-Stim, 5 consecutive days of brief bouts of high-load isometric contractions) while the other served as a SI control (SI). Both the medial gastrocnemius (MG) and soleus weights (relative to body weight) were approximately 71% of Con in the SI, but maintained at Con in the SI-Stim group. Activity of the IGF-1/phosphatidylinositol 3-kinase (PI3K)/Akt pathway of protein synthesis was similar among all groups in the MG. Expression of atrogin-1 and muscle RING finger-1 (MuRF-1), markers of protein degradation, were higher in the MG and soleus of the SI than Con and maintained at Con in the SI-Stim. Compared with Con, the anti-growth factor myostatin was unaffected in the MG and soleus in the SI but was lower in the MG of the SI-Stim. These results demonstrate that upregulation of specific protein catabolic pathways plays a critical role in SI-induced atrophy, while this response was blunted by 4 min of daily high-resistance electromechanical stimulation and was able to preserve most of the muscle mass. Although the protein anabolic pathway (IGF-1/PI3K/Akt) appears to play a minor role in regulating mass in the SI model, increased translational capacity may have contributed to mass preservation in response to isometric contractions.

Electromechanical stimulation ameliorates inactivity-induced adaptations in the medial gastrocnemius of adult rats.

The efficacy of high-load, short-duration isometric contractions, delivered as one vs. two sessions per day, on blunting inactivity-induced adaptations in the medial gastrocnemius (MG) were compared. Adult rats were assigned to a control (Con) or spinal cord-isolated (SI) group where one limb was stimulated (SI-Stim) while the other served as a SI control (SI-C). One bout of stimulation (BION microstimulator) consisted of a 100-Hz, 1-s stimulus, delivered every 30 s for 5 min with a 5-min rest period. This bout was repeated six times consecutively (SI-Stim1) or with a 9-h rest interval after the third bout (SI-Stim2) for 30 consecutive days. MG weights (relative to body weight) were 63, 72, and 79% of Con in SI-C, SI-Stim1, and SI-Stim2, respectively. Mean fiber size was 56% smaller in SI-C than in Con, and it was 19 and 31% larger in SI-Stim1 and SI-Stim2, respectively, compared with SI-C. Maximum tetanic tension was 42, 60, and 73% of Con in SI-C, SI-Stim1, and SI-Stim2, respectively. Specific tension was 77% of Con in SI-C, and at Con levels in both SI-Stim groups. SI increased the percent IIb myosin heavy chain composition (from 49 to 77%) and IIb+ fibers (from 63 to 79%): these adaptations were prevented by both Stim paradigms. These results demonstrate that 1) brief periods of high-load isometric contractions are effective in reducing inactivity-induced atrophy, functional deficits, and phenotypic adaptations in a fast hindlimb extensor, and 2) the same amount of stimulation distributed in two compared with one session per day is more effective in ameliorating inactivity-related adaptations.

Rehabilitative therapies after spinal cord injury.

We review some basic and highly relevant concepts in the effort to develop improved rehabilitative interventions for subjects with spinal cord injury (SCI). Interventions that are likely to contribute to improved sensorimotor function include (1) practice of the specific motor task that needs to be improved; and (2) combining the training with one or more interventions--such as pharmacological modulation of the excitability of spinal neural networks, implantation of selected cell types such as olfactory ensheathing glia (OEG), and/or modulation of the excitability of the spinal cord via epidural stimulation. Upon improvement of the neural control of the musculature following SCI, it will always be prudent to maximize the torque output from these activation patterns by assuring that muscle mass is maintained. Therefore, it seems quite feasible that considerable improvement in locomotor performance can be achieved by improved coordination of motor pools, as well as effective recovery of muscle mass, which will assist in the potential generation of normal forces among agonistic and antagonistic muscle groups.