Mesenchymal stromal cell therapy for patients with rheumatoid arthritis.

Management of relapses and refractory rheumatoid arthritis (RA) patients is complex and difficult. Even after the administration of new biological disease-modifying anti-rheumatic drugs (DMARDs), only a few patients achieve the complete remission phase. DMARDs help only in modifying the disease activity, which sooner or later fails. They do not manage the disease at the patho-etiological level. There are some serious side effects as well as drug interaction with DMARDs. There are few subsets of RA patients who do not respond to DMARDs, reasons unknown. Mesenchymal stem cells (MSCs) provide a promising alternative, especially in such cases. This review elaborates on the studies pertaining to the application of MSCs in rheumatoid arthritis over the last two decades. A total of 14 studies (one review article) including 447 patients were included in the study. Most of the studies administered MSCs in refractory RA patients through the intravenous route with varied dosages and frequency of administration. MSCs help in RA treatment via various mechanisms including paracrine effects. All the studies depicted a better clinical outcome with minimal adverse events. The functional scores including the VAS scores improved significantly in all studies irrespective of dosage and source of MSCs. The majority of the studies depicted no complications. Although the use of MSCs in RA is still in the early stages requiring further refinement in the source of MSCs, dosage, and frequency. The role of MSCs in the management of RA has a promising prospect. MSCs target the RA at the molecular level and has the potential to manage refractory RA cases not responding to conventional treatment. Multicentric, large sample populations, and long-term studies are required to ascertain efficacy and safety.

A randomized controlled trial of propofol-remifentanil total intravenous anesthesia and sevoflurane-fentanyl anesthesia on early postoperative fatigue in patients undergoing laparoscopic colorectal surgery.

PURPOSE: Even after uncomplicated surgery, postoperative fatigue prevalence has been reported to be 30-80% for various surgeries. We evaluated postoperative fatigue according to anesthetic technique in patients who underwent colorectal surgery. METHODS: One hundred thirty patients who underwent colorectal surgery were randomly assigned to either propofol-remifentanil total intravenous anesthesia (propofol-remifentanil group, n = 65) or sevoflurane-fentanyl anesthesia (sevoflurane-fentanyl group, n = 65). The primary outcome was the prevalence of postoperative fatigue, as defined by the Chalder Fatigue Questionnaire (total score ≥ 16), at 24 h postoperatively. Secondary outcomes were early postoperative complications during hospitalization and laboratory examination. RESULTS: The final analyses included 127 patients. The prevalence of postoperative fatigue on the 1st postoperative day was lower in the propofol-remifentanil group than the sevoflurane-fentanyl group: 56.3% (36/64) in the propofol-remifentanil group and 73.0% (46/63) in the sevoflurane-fentanyl group (relative risk [RR] = 0.77, 95% confidence interval [CI] 0.59-1.00; P = 0.048). However, there was no difference between the two groups in postoperative fatigue at postoperative day 3. Other postoperative outcomes including the severity of pain and the incidence of nausea/vomiting were not different between the two groups, but postoperative atelectasis on chest X-ray was higher in the sevoflurane-fentanyl group (2/64 [3.1%] vs. 9/63 [14.3%], P = 0.025). C-reactive protein change from preoperative to postoperative day 1 and 5 was significantly lower in the propofol-remifentanil group (P = 0.044). CONCLUSION: Propofol-remifentanil total intravenous anesthesia was associated with reduced postoperative fatigue at the 1st postoperative day compared with sevoflurane-fentanyl anesthesia. Clinical trial The Korean Clinical Research Registry (study identifier: KCT0006917, principal investigator's name: MiHye Park, date of registration: January 12, 2022).

MicroRNA-135b-5p Is a Pathologic Biomarker in the Endothelial Cells of Arteriovenous Malformations.

Arteriovenous malformations (AVMs) are congenital vascular anomalies with a poor prognosis. AVMs are considered intractable diseases, as there is no established approach for early diagnosis and treatment. Therefore, this study aimed to provide new evidence by analyzing microRNAs (miRNAs) associated with AVM. We present fundamental evidence for the early diagnosis and treatment of AVM by analyzing miRNAs in the endothelial cells of AVMs. This study performed sequencing and validation of miRNAs in endothelial cells from normal and AVM tissues. Five upregulated and two downregulated miRNAs were subsequently analyzed under hypoxia and vascular endothelial growth factor (VEGF) treatment by one-way analysis of variance (ANOVA). Under hypoxic conditions, miR-135b-5p was significantly upregulated in the AVM compared to that under normal conditions, corresponding to increased endothelial activity (p-value = 0.0238). VEGF treatment showed no significant increase in miR-135b-5p under normal conditions, however, a surge in AVM was observed. Under both hypoxia and VEGF treatment, comparison indicated a downregulation of miR-135b-5p in AVM. Therefore, miR-135b-5p was assumed to affect the pathophysiological process of AVM and might play a vital role as a potential biomarker of AVMs for application related to diagnosis and treatment.

Three-dimensional culture conditioned bone marrow MSC secretome accelerates wound healing in a burn injury mouse model.

Mesenchymal stem cell (MSC)-based therapy has emerged as a promising regenerative therapeutic approach for wound healing. To determine the effects of cultured MSCs as a 2D monolayer (2D-MSCs) and 3D spheroids (3D-MSCs) on their secretomes, and to examine the effect of 3D-MSC secretomes on endothelial cells (ECs) and MSCs in a burn injury mouse model. MSCs were cultured as 2D monolayers (2D-MSCs) and 3D spheroids (3D-MSCs) and their cellular characteristics were evaluated by western blotting. 2D-MSC and 3D-MSC secretomes (condition medium: CM) were analyzed using an angiogenic array. The activation of ECs by 2D-MSC and 3D-MSC CMs was examined in cellular proliferation, migration, and tube formation assays. The wound healing effects of 2D-MSCs and 3D-MSCs were determined in vivo using a burn injury mouse model. 3D culture conditions altered the markers of components that regulate cell survival, cytoskeletal, adhesion, and proliferation. Interleukin-6 (IL-6), vascular endothelial growth factor A (VEGFA), IL-8, and chemokine (CXC motif) ligand 1 (CXCL1) were present at high levels in the CM of 3D-MSCs compared with 2D-MCs. 3D-MSC-CMs promoted the proliferation, migration, and tube formation of ECs. Furthermore, 3D-MSC treatment enhanced wound healing in a burn injury mouse model. 3D culture improves proangiogenic factors in the MSC secretome and 3D-MSCs represent a new cell-based treatment strategy for wound healing.

Comparison of the perfusion index as an index of noxious stimulation in monitored anesthesia care of propofol/remifentanil and propofol/dexmedetomidine: a prospective, randomized, case-control, observational study.

BACKGROUND: Dexmedetomidine, one of the sedatives, has an analgesic effect. We aimed to investigate postoperative analgesia with dexmedetomidine as adjuvants for procedural sedation using perfusion index (PI). METHODS: In this prospective, randomized, case-control, observational study, 72 adult patients, 19-70 years, who were scheduled for chemoport insertion under monitored anesthesia care were performed. According to the group assignment, remifentanil or dexmedetomidine was simultaneously infused with propofol. The primary outcome was PI 30 min after admission to the post anesthesia care unit (PACU). And, pain severity using numerical rating scale (NRS) score and the relationship between NRS score and PI were investigated. RESULTS: During PACU staying, PI values were significantly different between the two groups PI values at 30 min after admission to the PACU were 1.3 (0.9-2.0) in the remifentanil group and 4.5 (2.9-6.8) in the dexmedetomidine group (median difference, 3; 95% CI, 2.1 to 4.2; P < 0.001). The NRS scores at 30 min after admission to the PACU were significantly lower in the dexmedetomidine group (P = 0.002). However, there was a weak positive correlation between NRS score and PI in the PACU (correlation coefficient, 0.188; P = 0.01). CONCLUSION: We could not find a significant correlation between PI and NRS score for postoperative pain control. Using PI as a single indicator of pain is insufficient. TRIAL REGISTRATION: Clinical Trial Registry of Korea, https://cris.nih.go.kr : KCT0003501, the date of registration: 13/02/2019.

Chemical Burn Injury on the Cornea Following Skin Preparation With Chlorhexidine in Tonsillectomy and Adenoidectomy.

This article report discusses a pediatric patient who suffered a corneal chemical burn injury after tonsillectomy and adenoidectomy surgery due to skin preparation with chlorhexidine. In this case, inadequate sealing of the eye shield during skin preparation allowed the chlorhexidine-alcohol solution to accumulate at its edge and gradually penetrate, resulting in the corneal injury. Prompt ophthalmological intervention and appropriate eye care treatment led to a gradual improvement in the patient's symptoms. The authors aim to present the case, share the revisions made to our skin preparation policy, and emphasize the importance of cautious antiseptic use to minimize the risk of adverse events. Adverse effects of chlorhexidine, such as hypersensitivity reactions and burns, including corneal damage, are highlighted. Health care providers should exercise caution when selecting and applying antiseptics, considering patient-specific factors, and comprehensive training should be provided to promote adherence to safe antiseptic practices during surgical procedures.

Bilateral Nostril Abrasion in Endoscopic Sinus Surgery with Micodebrider.

The emergence of microdebrider technology has revolutionized endoscopic sinus surgery (ESS). Although widely used, it has been associated with complications such as cerebrospinal fluid leakage, ocular and brain injuries, and synechia formation. However, reports on cases of skin abrasion associated with the use of microdebriders in ESS are scarce. We herein present a unique observation of bilateral nostril abrasion after ESS using the microdebrider in a 53-year-old man. The patient underwent ESS and septoplasty for nasal obstruction and polyps. Bilateral nostril erythema and skin abrasion were observed after surgery, which resolved without scarring. Nostril abrasion is attributed to the lever-like use of the microdebrider against the medial aspect of the nostril during the procedure, particularly among inexperienced surgeons. This prompts the need for a cautious approach when using microdebriders in ESS to minimize complications. Increased awareness and precautionary measures can enhance the safety of microdebriders in ESS.

Influence of Transforming Growth Factors beta 1 and beta 3 in the Scar Formation Process.

BACKGROUND: Transforming growth factor-beta (TGF-ß) plays an instrumental role in forming scars and keloids. TGF-ß isoforms exhibit differential expression, indicating distinct wound healing and scar formation functions. However, the role of TGF-ß1 and TGF-ß3 in wound healing and scar formation remains unclear. This study aimed to compare the specific roles of TGF-ß1 and TGF-ß3 in wound healing and scar formation by biomolecular analysis. MATERIALS AND METHODS: The study was conducted by cell isolation and culture cells from a total of 20 human samples. Normal human fibroblasts (NHF) were isolated from normal human samples and myofibroblasts from the different scar types, namely hypertrophic (HT) and keloid (K) scars. NHF and cells from the HT, and K scar, each of which were divided into 3 sample groups: the untreated control, TGF-ß1 (10 µg/mL)-treated group, and TGF-ß3 (10 µg/mL)-treated group. The results of confocal microscopy and fluorescence-activated cell sorting experiments were compared. RESULTS: Both the HT and K groups had higher α-smooth muscle actin (α-SMA) expression than the NHF group in the untreated control group. In comparison with the untreated group, NHFs showed a significant increase in α-SMA expression in the TGF-ß1-treated group. HT showed a high α-SMA level, which was statistically significant compared with the normal fibroblasts. In the TGF-ß3-treated group, α-SMA expression was slightly increased in NHF as compared with the untreated group. TGF-ß3 treated HT exhibited a greater reduction in α-SMA expression than in the TGF-ß1 treated HT. K, on the other hand, had only a minimal effect on the treatment of TGF-ß1 and TGF-ß3. CONCLUSIONS: The findings suggest that TGF-ß3 may play a regulatory role in the wound repair process, which could be useful in the development of scar-reducing therapies for patients with scar-related cosmetic concerns.

Extracellular vesicles derived from fibroblasts promote wound healing by optimizing fibroblast and endothelial cellular functions.

Extracellular vesicles (EVs) have been exhibited as promising candidates for delivering endogenous therapeutic cargos for regenerative therapies. Fibroblasts could be candidate source cells for EVs, to investigate their therapeutic effects in wound healing. Here we demonstrated the isolation and characterization of fibroblast-derived (L929 cell line) EVs (L929-EVs). Furthermore, L929-EVs treatment showed pro-wound healing effects in vitro by enhancing proliferation, migration, and scarless wound healing related genes in fibroblast cells. L929-EVs treatment also enhanced the migration and tube formation of endothelial cells. The combination of L929-EVs with fibrin glue accelerated wound healing in the mouse skin wound model by enhancing collagen formation, collagen maturation, and blood vessels in the wounded skin. The role of fibroblast-derived EVs in wound healing could be an important phenomenon, and fibroblast-derived EVs could be harnessed for wound healing therapies.

Simulation Analysis of Flow Rate Variability During Microinfusions: The Effect of Vertical Displacement and Multidrug Infusion in Conventional Infusion Pumps Versus New Cylinder-Type Infusion Pumps.

BACKGROUND: Medication dosing errors can occur during microinfusions when there is vertical pump displacement or multidrug infusion through a single intravenous path. We compared flow rate variability between new-generation cylinder-type infusion pumps and conventional infusion pumps under simulated conditions. METHODS: We evaluated the flow rates during microinfusions using different infusion pumps (syringe pump with 10/30/50-mL syringes, peristaltic pump, and cylinder pump). Two visible dyes were used as model drugs. The study samples were quantified using spectrophotometry. For vertical displacement, the infusion pumps were moved up and down by 60 cm during microinfusions at 0.5 mL·h-1 and 2 mL·h-1. In the multi-infusion study, the second drug flow was added through 4 linearly connected stopcocks either upstream or downstream of the first drug. We compared the total error dose between the cylinder pump and the syringe pump with a Mann-Whitney U test and additionally estimated the effects of the infusion pumps on total error doses by linear regression analysis. RESULTS: There were repetitive patterns of temporary flow increases when the pump was displaced upward and flow decreases when the pump was displaced downward in all settings. However, the amount of flow irregularities was more pronounced at the lower infusion rate and in the syringe-type pump using larger volume syringes. The total error dose increased in the syringe pump loaded with a 50-mL syringe compared to that of the new cylinder pump (regression coefficient [ß] = 4.66 [95% confidence interval {CI}, 1.60-7.72]; P = .008). The initiation and cessation of a new drug during multidrug microinfusion in the same intravenous path affected the lower rate first drug leading to a transient flow rate increase and decrease, respectively. The change in flow rate was observed regardless of the port selected for addition of the second drug, and the total error dose of the first drug did not significantly vary when an upstream or a downstream port was selected. CONCLUSIONS: In the microinfusion settings, attention must be paid to the use of the syringe pump loaded with large-volume syringes. The novel cylinder pump could be considered as a practical alternative to syringe pumps with small syringes given its flow stability without the need for frequent drug replacement.

MicroRNA-365a/b-3p as a Potential Biomarker for Hypertrophic Scars.

The clinical aspects of hypertrophic scarring vary according to personal constitution and body part. However, the mechanism of hypertrophic scar (HS) formation remains unclear. MicroRNAs (miRNAs) are known to contribute to HS formation, however, their detailed role remains unknown. In this study, candidate miRNAs were identified and analyzed as biomarkers of hypertrophic scarring for future clinical applications. HSfibroblasts and normal skin fibroblasts from patients were used for profiling and validation of miRNAs. An HS mouse model with xenografted human skin on nude mice was established. The miRNA expression between normal human, normal mouse, and mouse HS skin tissues was compared. Circulating miRNA expression levels in the serum of normal mice and mice with HSs were also analyzed. Ten upregulated and twenty-one downregulated miRNAs were detected. Among these, miR-365a/b-3p and miR-16-5p were identified as candidate miRNAs with statistically significant differences; miR-365a/b-3p was significantly upregulated (p = 0.0244). In mouse studies, miR-365a/b-3p expression levels in skin tissue and serum were higher in mice with HSs than in the control group. These results indicate that miRNAs contribute to hypertrophic scarring and that miR-365a/b-3p may be considered a potential biomarker for HS formation.

Hypoxia Promotes Angiogenic Effect in Extracranial Arteriovenous Malformation Endothelial Cells.

Arteriovenous malformation (AVM) is characterized by high-flow blood vessels connecting arteries and veins without capillaries. This disease shows increased angiogenesis and a pathophysiological hypoxic environment in proximal tissues. Here, we analyzed the effects of hypoxia on angiogenesis in the endothelial cells (ECs) of AVM and normal tissues. ECs from human normal and AVM tissues were evaluated using immunocytochemistry with CD31. In vitro tube formation under hypoxia was tested in both ECs using Matrigel. The relative expression of angiogenesis-related genes was measured using real-time PCR. Under normoxia, CD31 was significantly higher in AVM ECs (79.23 ± 0.65%) than in normal ECs (74.15 ± 0.70%). Similar results were observed under hypoxia in AVM ECs (63.85 ± 1.84%) and normal ECs (60.52 ± 0.51%). In the tube formation test under normoxic and hypoxic conditions, the junction count and total vessel length were significantly greater in AVM ECs than normal ECs. Under both normoxia and hypoxia, the angiogenesis-related gene FSTL1 showed a significantly higher expression in AVM ECs than in normal ECs. Under hypoxia, CSPG4 expression was significantly lower in AVM ECs than in normal ECs. Accordingly, the angiogenic effect was increased in AVM ECs compared with that in normal ECs. These results provide a basic knowledge for an AVM treatment strategy.

Oscillatory shear stress promotes angiogenic effects in arteriovenous malformations endothelial cells.

BACKGROUND: Vascular endothelial cells (ECs) are subject to continuous shear stress due to blood circulation. Mechanical stress due to high shear flow can also cause arteriovenous malformation (AVM) when ECs respond hyper-sensitively to shear flow. This study was conducted to test the hypothesis that angiogenesis could be promoted in response to mechanical stress via regulation of pro-angiogenic factors in AVM cells. METHODS: ECs were extracted from the tissue samples from six AVM patients and six normal patients. Shear stress at 7 dynes/cm2 were applied for 24 h. Before and after application of shear stress to each group, RT-PCR was performed to access the expression levels of angiopoietin2(AGP2), aquaporin1(AQP1) and TGFßR1. Immunofluorescences was also performed to evaluate the level of protein expressions. RESULTS: In both normal and AVM tissues, AGP2 and TGFßR1 under the shear stress showed increased expression in the ECs compared to the non-sheared samples. When AVMs and normal arterial vasculature were compared, the expression levels of both AGP2 and TGFßR1 in AVMs were higher when compared to normal arterial vasculature with or without shear stress. Immunofluorescence-based protein analysis also confirmed shear-induced AGP2 and TGFßR1 in both samples of normal and AVM patients. CONCLUSIONS: AVMs exhibited higher sensitivity to shear stress by producing higher expressions of some marked genes and proteins that regulate the endothelial functions upon exposure to shear stress. While the physiological mechanism for AVMs remain elusive, our study shows the plausibility of physical stress imposed by the shearing flow can cause the occurrence of AVMs.

Effects of prophylactic atropine on the time to tracheal intubation with the pre-administration of remifentanil.

BACKGROUND: Pre-administration of remifentanil in target-controlled propofol and remifentanil anaesthesia could prolong the time of onset of muscle relaxation owing to haemodynamic effects, thereby prolonging the time to tracheal intubation. Although the sympatholytic effects of remifentanil result in bradycardia and hypotension, these responses can be attenuated by the administration of atropine. Therefore, we investigated whether prophylactic administration of atropine could prevent the prolongation of the time to tracheal intubation. METHODS: Sixty-four patients were included in this study. They were randomised into Group A (atropine 0.5 mg, n = 32) and Group S (saline 0.9%, n = 32), immediately before the pre-administration of remifentanil. The primary outcome was the time to tracheal intubation and the secondary outcomes were rocuronium onset time, time to loss of consciousness (LOC), time to reach a value of 60 on the bispectral index (BIS) and haemodynamic variables. RESULTS: The median [Interquartile range] of the time to tracheal intubation was 240 [214, 288]s in Group S and 190 [176, 212]s in Group A(median difference: 50 s, 95% confidence interval: 27-80 s, P = .001). Rocuronium onset time was significantly decreased in Group A compared to that in Group S (129 [110, 156] vs 172 [154, 200], P = .001). The times to LOC and reach 60 on the BIS were not significantly different between the two groups. Cardiac output(CO) and heart rate were less decreased in Group A than in Group S (P = .02, P < .001, respectively). CONCLUSIONS: Prophylactic administration of atropine could compensate for the reduction in CO in cases pre-administered with remifentanil in target-controlled propofol and remifentanil anaesthesia. This in turn prevented the prolongation of rocuronium onset time and reduced the time to tracheal intubation.

Osteogenesis of 3D-Printed PCL/TCP/bdECM Scaffold Using Adipose-Derived Stem Cells Aggregates; An Experimental Study in the Canine Mandible.

Three-dimensional (3D) printing is perceived as an innovative tool for change in tissue engineering and regenerative medicine based on research outcomes on the development of artificial organs and tissues. With advances in such technology, research is underway into 3D-printed artificial scaffolds for tissue recovery and regeneration. In this study, we fabricated artificial scaffolds by coating bone demineralized and decellularized extracellular matrix (bdECM) onto existing 3D-printed polycaprolactone/tricalcium phosphate (PCL/TCP) to enhance osteoconductivity and osteoinductivity. After injecting adipose-derived stem cells (ADSCs) in an aggregate form found to be effective in previous studies, we examined the effects of the scaffold on ossification during mandibular reconstruction in beagle dogs. Ten beagles were divided into two groups: group A (PCL/TCP/bdECM + ADSC injection; n = 5) and group B (PCL/TCP/bdECM; n = 5). The results were analyzed four and eight weeks after intervention. Computed tomography (CT) findings showed that group A had more diffuse osteoblast tissue than group B. Evidence of infection or immune rejection was not detected following histological examination. Goldner trichrome (G/T) staining revealed rich ossification in scaffold pores. ColI, Osteocalcin, and Runx2 gene expressions were determined using real-time polymerase chain reaction. Group A showed greater expression of these genes. Through Western blotting, group A showed a greater expression of genes that encode ColI, Osteocalcin, and Runx2 proteins. In conclusion, intervention group A, in which the beagles received the additional ADSC injection together with the 3D-printed PCL/TCP coated with bdECM, showed improved mandibular ossification in and around the pores of the scaffold.

Effects of inspired oxygen concentration during emergence from general anaesthesia on postoperative lung impedance changes evaluated by electrical impedance tomography: a randomised controlled trial.

We evaluated the effects of three different inspired oxygen concentrations (40%, 80%, and 100%) at anaesthesia emergence on postoperative lung volumes as measured by global impedance of electrical impedance tomography (EIT). This is a randomised, controlled, and assessor-blinded study in single-centre from May 2017 to August 2017. Seventy-one patients undergoing elective laparoscopic colorectal surgery with healthy lung condition were randomly allocated into the three groups based on the concentration of inspired oxygen applied during anaesthesia emergence: 40%-, 80%- or 100%-oxygen. End-expiratory lung impedance (EELI) with normal tidal ventilation and total lung impedance (TLI) with full respiratory effort were measured preoperatively and before discharge in the post-anaesthesia care unit by EIT, and perioperative changes (the ratio of difference between preoperative and postoperative value to preoperative value) were compared among the three groups. Postoperative lung impedances were significantly reduced compared with preoperative values in all patients (P < 0.001); however, perioperative lung impedance reduction (%) did not differ among the three oxygen groups. The mean reduction ratio in each 40%-, 80%-, and 100%-oxygen group were 37% ± 13%, 41% ± 14%, and 46% ± 14% for EELI (P = 0.125) and 40% ± 20%, 44% ± 17% and 49% ± 20% for TLI (P = 0.276), respectively. Inspired oxygen concentrations applied during anaesthesia emergence did not show a significant difference in postoperative lung volume as measured by EIT in patients undergoing laparoscopic colorectal surgery with healthy lungs.Trial registration cris.nih.go.kr (KCT0002642).

Effect of Keratinocytes on Myofibroblasts in Hypertrophic Scars.

Myofibroblasts play a central role in matrix formation and wound contraction during wound healing and undergo apoptosis at the end of the healing. Hypertrophic scarring is a pathologic condition in which myofibroblasts persist in the tissue. It has been hypothesized that abnormalities in epidermal-dermal crosstalk underlie this pathology. Therefore, in this study, we investigated whether myofibroblasts are affected by keratinocytes. Transforming growth factor beta-induced myofibroblasts (Imyo) and myofibroblasts from hypertrophic scar tissue (Hmyo) were characterized using microarrays. Keratinocytes were co-cultured with myofibroblasts, and quantitative PCR analysis was performed. We found that numerous extracellular matrix- and smooth muscle cell-associated genes were upregulated in Imyo and Hmyo respectively, and these findings suggest that Hmyo are fully differentiated myofibroblasts and that Imyo are less differentiated than Hmyo. Decreased collagen type 1 gene expression was found in keratinocytes co-cultured with Imyo and Hmyo; further, α-smooth muscle actin expression in Imyo increased in the presence of keratinocytes. These observations indicate that keratinocytes play a role in the development of pathological fibrosis in hypertrophic scar tissue by regulating the behavior of dermal fibroblasts and myofibroblasts. We believe that this study provides the basis for understanding the pathophysiology of hypertrophic scarring and identifying new therapeutic approaches for this dysfunction.No Level Assigned This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors - www.springer.com/00266 .

Body volume, body fatness, and metabolic syndrome.

Body volume by three-dimensional body scanning (3DBS) may be an alternative index for evaluating body fatness. The aim of this study was to evaluate the association of body volume with body fatness and metabolic syndrome. This study included 38 Korean women whose body volume was measured using 3DBS. We measured body fatness using dual-energy X-ray absorptiometry and computed tomography. Participants with metabolic syndrome were defined as having three or more of the following components: high blood pressure (≥130/85 mmHg), elevated fasting glucose (≥100 mg/dl), hypertriglyceridemia (≥150 mg/dl), low high-density lipoprotein-cholesterol (<50 mg/dl), and abdominal obesity measured by waist circumference ≥80 cm. Total body, trunk, lower trunk, and limb volumes were significantly correlated with body mass index, waist circumference, total fat mass, percentage body fat, and abdominal fat areas. After adjustment for age, current smoking, at-risk drinking, and physical inactivity, the odds ratios (95% confidence intervals) for metabolic syndrome associated with total body, trunk, lower trunk, and limb volume were 1.08 (1.01-1.16), 1.11 (1.01-1.22), 1.20 (1.01-1.43), and 1.31 (1.04-1.66), respectively. Body volume by 3DBS was significantly associated with body fatness and metabolic syndrome. 3DBS may be a useful tool for detecting and monitoring body fatness and metabolic syndrome.

Expression Patterns of HIF-1α Under Hypoxia in Vascular Smooth Muscle Cells of Venous Malformations.

PURPOSE: The molecular pathophysiology of venous malformations (VMs), which are a type of vascular malformation, is poorly understood. Until now, it is known that VM lesions are related to the process of angiogenesis. Because angiogenesis is induced under hypoxic conditions, hypoxia is thought to be important in VM lesion formation. Therefore, we examined the implications of hypoxia on the biological behavior of VM vascular smooth muscle cells (VSMCs). In doing so, we investigated the expression patterns of hypoxia-inducible factor-1α (HIF-1α), which plays a key role in hypoxia-induced angiogenesis, to provide a further understanding of the molecular mechanisms involved in VM. METHODS: Vascular smooth muscle cells from 5 normal veins and 5 VM lesions were cultured under moderate hypoxic conditions (3% O2, 5% CO2). The effects of hypoxia on HIF-1α expression were measured by immunocytochemical staining, reverse transcription-polymerase chain reaction, and real-time reverse transcription-polymerase chain reaction. RESULTS: Overall, the expression of HIF-1α in cells was high after exposure to hypoxia for 6 or 12 hours, but decreased after 24 hours of hypoxia. HIF-1α expression in VM VSMCs was 2 times higher than that in normal VSMCs. Immunocytochemically, HIF-1α was mainly located in the nucleus and the intensity in VM VSMCs was stronger after 6 and 12 hours of hypoxia when compared to the expression pattern of HIF-1α in VSMCs from normal tissue. This suggested that VM tissue is more susceptible to the effects of hypoxia than normal tissue. CONCLUSIONS: These results indicate that the high expression of HIF-1α in VM VSMCs under hypoxic conditions could be an important factor for stimulating downstream angiogenesis in VM. Furthermore, the results of this investigation could provide the basis for future studies of VM pathophysiology, and ultimately lead to the development of new therapeutic approaches.

A prospective, randomized, double-blind, multicenter trial to evaluate the therapeutic efficacy and safety of palonosetron in the treatment of postoperative nausea and vomiting over a 72-h period.

PURPOSE: We performed a multicenter, randomized, double-blind trial to assess the efficacy and safety of a single, fixed, intravenous dose of palonosetron (0.075 mg) in the treatment of established postoperative nausea and vomiting (PONV). METHODS: Three hundred and eighty-four patients who had at least one risk factors of PONV and underwent surgery under general anesthesia were screened. Those who developed PONV were randomized to receive either 0.075 mg intravenous palonosetron or a placebo. The incidence of nausea and vomiting, severity of nausea, requirements for rescue anti-emetics, and adverse effects at 2, 24, and 72 h after drug administration were evaluated. Complete response (CR) and complete control (CC) rate were compared for 24 and 72 h. RESULTS: Among the 384 patients, 152 (39.6 %) developed PONV and were randomized to either the palonosetron (n = 75) or placebo (n = 77) group. The number of patients with CR at 24 and 72 h was higher in the palonosetron group than the placebo group [0-24 h: n = 49 (68.1 %) vs. n = 30 (40.5 %), p < 0.001; 0-72 h: n = 47 (65.3 %) vs. n = 28 (37.8 %), p < 0.001]. The incidence of PONV at 2, 24, and 72 h periods was lower in the palonosetron group than the placebo group (29.2, 45.8, and 50.0 % in the palonosetron group vs. 50.0, 62.2, and 66.2 % in the placebo group, p = 0.010, 0.048, 0.047, respectively). The incidence of adverse events was not different between the groups. CONCLUSION: A single 0.075 mg IV dose of palonosetron effectively increased the CR rates at 24 and 72 h in these moderate-risk patients with established PONV.