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Biomedical subjects

K Fujioka

Publications and source records attributed to K Fujioka.

At least 37 records · Page 2Linked to original sources
PubMed2000

Is endovascular treatment of abdominal aortic aneurysms less invasive regarding the biological responses?

To compare the biological responses following an endoluminal repair and a conventional open repair of abdominal aortic aneurysm (AAA), 14 patients who underwent an endoluminal repair (endograft group) and 26 who underwent an open repair (open group) were investigated. As markers of biological responses, interleukin-6 (IL-6) and -8 (IL-8), granulocyte elastase (GEL), white blood cell count (WBC), and serum C-reactive protein (CRP) were all measured preoperatively as well as on postoperative days (POD) 1, 3, and 6. In addition, the blood loss, duration of surgery, initial oral intake the day after surgery, and length of hospital stay were compared between both groups. The plasma levels of IL-6, GEL, CRP, and WBC were higher in the endograft group than in the open group, while the CRP, WBC, and GEL levels all peaked on POD 3. The plasma level of IL-6 remained high in the endograft group, compared with that in the open group throughout the study period. Conversely, blood loss, initial oral intake the day after surgery, and the length of hospital stay were all significantly greater in the open group than in the endograft group, although there was no significant difference in the duration of surgery between the two groups. These findings indicate that although the endoluminal repair of AAA is supposed to be less invasive, the biological responses tend to be greater because of the manipulation related to the insertion of the stent graft.

Adult↗
PubMed2000

Weight loss with sibutramine improves glycaemic control and other metabolic parameters in obese patients with type 2 diabetes mellitus.

AIM: To determine the efficacy and tolerability of sibutramine hydrochloride in obese patients whose type 2 diabetes was poorly controlled on diet alone or with an oral antidiabetic agent. METHODS: This study was a 24-week, double-blind, multicentre trial following a 5-week placebo run-in period. One hundred and seventy-five obese (body mass index (b.m.i.) > or =27 kg/m2) patients with poorly controlled type 2 diabetes mellitus were randomized either to sibutramine (n = 89; mean age 53.5 years; mean weight 99.3 kg) or placebo (n = 86; mean age 55 years; mean weight 98.2 kg) at 16 participating centres. To achieve moderate calorie restriction (deficit > or = 250-500 kcal/day), individual dietary counselling was accompanied by either placebo or sibutramine (initial dosage of 5 mg/day titrated up by 5 mg biweekly through week 6, and maintained at 20 mg through week 24). The main outcome measures included changes in weight, b.m.i., waist and hip circumference, glycaemic control, lipid profile, and quality of life, and evaluation of reported adverse events. RESULTS: Sixty-seven per cent of sibutramine patients and 71% of placebo patients completed the study. At week 24 when comparing those who completed the course, sibutramine compared with placebo patients showed significantly greater (p < 0.001) absolute (-4.3 vs. -0.4 kg) and percentage (-4.5% vs. -0.5%) weight loss. Weight loss > or =5% or 10% was achieved by 33% and 8% of sibutramine patients, respectively, but no placebo patients (p < 0.03 or better). Improvement in glycaemic control was correlated with weight loss (p < 0.001). In 5% and 10% weight-loss responders, mean treatment differences were -0.53% and -1.65% (p < or = 0.05), respectively, for HbA1c, and -1.4 mmol/l (p < or =0.05) and -3.8 (p < or =0.05) mmol/l for fasting plasma glucose. Sibutramine patients also showed improvements in fasting insulin, triglycerides, HDL cholesterol, and quality-of-life assessments. Overall, sibutramine was well tolerated compared with the placebo. Sibutramine treatment was associated with small mean increases in blood pressure (BP) and pulse, although an increase in BP was not seen in sibutramine-treated patients who lost > or = 5% of their weight. CONCLUSIONS: Sibutramine produced statistically and clinically significant weight loss when used in combination with recommendations for moderate caloric restriction. This weight loss was associated with improvements in metabolic control and quality of life, and sibutramine was generally well tolerated in obese patients with type 2 diabetes.

Adolescent↗
PubMed2000

Human tissue distribution of TA02, which is homologous with a new type of aspartic proteinase, napsin A.

The N-terminal amino acid sequence of TA02 (molecular weight 35.0 kDa, isoelectric point 5.29), which is associated with primary lung adenocarcinoma, was determined and a fragment peptide was used to generate mouse monoclonal antibodies (mAbs) against TA02. The amino acid sequence suggested that TA02 might be homologous with napsin A, a new type of aspartic proteinase. In this context, we confirmed the expression of napsin A in primary lung adenocarcinoma using reverse-transcription polymerare chain reaction (RT-PCR) and showed that the TA02 mAbs reacted with glutathione-S-transferase (GST)-napsin A fusion protein. We concluded that TA02 is the same molecule as napsin A, and showed immunohistochemically that it is distributed mainly in type II pneumocytes, alveolar macrophages, renal tubules and exocrine glands and ducts in the pancreas. In particular, type II pneumocytes and alveolar macrophages showed high expression of TA02 among human normal tissues. In primary lung adenocarcinoma, 47 out of 58 (81.0%) primary lesions were positive. All well-differentiated adenocarcinomas except those of goblet cell type showed high expression of TA02. In addition, two out of seven (28.6%) large cell carcinomas showed low expression of TA02. The other histopathological types of primary lung cancer did not express TA02 at all. A few cases of renal cell cancer, pancreatic cancer, breast cancer, thyroid cancer, colon cancer and ovarian cancer showed low expression, but the staining patterns were completely different from that of primary lung adenocarcinoma, which showed a granular staining pattern. Our novel mAbs should be valuable for immunochemical detection of TA02/napsin A.

Adenocarcinoma↗
PubMed1999

Microstructure and release characteristics of the minipellet, a collagen-based drug delivery system for controlled release of protein drugs.

We have developed the minipellet, a matrix-type system for the sustained delivery of protein drugs using collagen as a biodegradable drug carrier. In this study, we analyzed the microstructure and release profile of the minipellet containing human serum albumin (HSA) as a model drug.The findings suggest that the minipellet has a structure in which collagen fibers are strongly oriented in the direction of extrusion from the nozzle in the molding process of the minipellet, and that HSA exists as fine particulate clusters which are homogeneously distributed among the collagen fibers in the minipellet. During release, the HSA clusters dissolve and HSA is retained within the collagen matrix as a solution.The results of release experiments indicate that HSA release from the minipellet is mainly controlled by diffusion in the collagen matrix, and that sustained release is achieved by the dense structure of the collagen matrix which is formed in the manufacture process. In addition, more detailed study suggests that the minipellet has unique directional release behavior caused by its microstructure.

Collagen↗
PubMed1999

Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial.

CONTEXT: The protein hormone leptin is important to the homeostatic regulation of body weight. Treatment with exogenous leptin may affect weight loss. OBJECTIVE: To determine the relationship between increasing doses of exogenous leptin administration and weight loss in both lean and obese adults. DESIGN: A randomized, double-blind, placebo-controlled, multicenter, escalating dose cohort trial conducted from April 1997 to October 1998. SETTING: Four university nutrition and obesity clinics and 2 contract clinical research clinics. PARTICIPANTS: Fifty-four lean (body mass index, 20.0-27.5 kg/m2; mean [SD] body weight, 72.0 [9.7] kg) and 73 obese (body mass index, 27.6-36.0 kg/m2; mean [SD] body weight, 89.8 [11.4] kg) predominantly white (80%) men (n = 67) and women (n = 60) with mean (SD) age of 39 (10.3) years. INTERVENTIONS: Recombinant methionyl human leptin self-administered by daily morning subcutaneous injection (0 [placebo], 0.01, 0.03, 0.10, or 0.30 mg/kg). In part A, lean and obese subjects were treated for 4 weeks; in part B, obese subjects were treated for an additional 20 weeks. Lean subjects consumed a eucaloric diet to maintain body weight at the current value, and obese subjects were prescribed a diet that reduced their daily energy intake by 2100 kJ/d (500-kcal/d) from the amount needed to maintain a stable weight. MAIN OUTCOME MEASURES: Body weight, body fat, and incidence of adverse events. RESULTS: Weight loss from baseline increased with increasing dose of leptin among all subjects at 4 weeks (P = .02) and among obese subjects at 24 weeks (P = .01) of treatment. Mean (SD) weight changes at 4 weeks ranged from -0.4 (2.0) kg for placebo (n = 36) to -1.9 kg (1.6) kg for the 0.1 mg/kg dose (n = 29). Mean (SD) weight changes at 24 weeks ranged from -0.7 (5.4) kg for the 0.01 mg/kg dose (n = 6) to -7.1 (8.5) kg for the 0.30 mg/kg dose (n = 8). Fat mass declined from baseline as dose increased among all subjects at 4 weeks (P = .002) and among obese subjects at 24 weeks of treatment (P = .004); more than 95% of weight loss was fat loss in the 2 highest dose cohorts at 24 weeks. Baseline serum leptin concentrations were not related to weight loss at week 4 (P = .88) or at week 24 (P = .76). No clinically significant adverse effects were observed on major organ systems. Mild-to-moderate reactions at the injection site were the most commonly reported adverse effects. CONCLUSIONS: A dose-response relationship with weight and fat loss was observed with subcutaneous recombinant leptin injections in both lean and obese subjects. Based on this study, administration of exogenous leptin appears to induce weight loss in some obese subjects with elevated endogenous serum leptin concentrations. Additional research into the potential role for leptin and related hormones in the treatment of human obesity is warranted.

Adult↗
PubMed1999

Effects of recombinant thrombopoietin on the growth of murine primitive and committed hematopoietic progenitors in serum-free culture.

BACKGROUND: The aim of the present study was to determine the effect of thrombopoietin (Tpo) in combination with other cytokines on the growth of murine megakaryocytic, granulocyte-macrophage, erythroid and primitive hematopoietic progenitor cells, excluding possibilities of synergistic effects by serum factor(s). METHODS: Serum-free clonogenic assay systems were used for assay of colony forming units in megakaryocytes (CFU-Mk), colony forming units in granulocytes-macrophages (CFU-GM), burst-forming units in erythrocytes (BFU-E) in marrow of normal mice and of high proliferative potential colony forming cells in 5-fluorouracil-treated marrow. RESULTS: Serum-free culture enabled megakaryocyte colony growth by recombinant murine (rm) Tpo and this was synergistically supported with rm interleukin (IL)-3, rm stem cell factor (SCF) or recombinant human (rh) erythropoietin (Epo). Recombinant human IL-6, rhIL-11 and rm granulocyte-macrophage colony stimulating factor (GM-CSF) showed synergistic effects with rmTpo only in the presence of serum. Recombinant murine IL-3 or rmSCF increased the large colonies and mixed-type colonies containing other populations, suggesting that these cytokines promoted the proliferation of immature populations of CFU-Mk. The rmTpo enhanced the growth of granulocyte-macrophage (GM) colonies stimulated by rmGM-CSF or rmIL-3 and erythroid bursts by rhEpo, with or without rmIL-3. The rmTpo also significantly increased HPP colonies in synergy with rmIL-3 only in the presence of serum or rmSCF. CONCLUSION: Serum-free culture is valuable for evaluating synergistic effects of cytokines and Tpo acts not only on megakaryocytic progenitors but also on granulocyte-macrophage, erythroid and primitive progenitor cells in combination with other cytokines, such as rmIL-3 and rmSCF. However, serum or SCF was required for enhancement of the colony growth of primitive progenitors by Tpo.

Animals↗
PubMed1999

Deletion polymorphism in the gene for angiotensin-converting enzyme is not a risk factor predisposing to abdominal aortic aneurysm.

OBJECTIVE: to establish whether deletion of the angiotensin-converting enzyme (ACE) gene is a risk factor predisposing to abdominal aortic aneurysm (AAA) or not. METHODS: the study included 125 patients with AAA and 153 controls randomly selected from 328 individuals. The control subjects were confirmed not to have an AAA, but matched with the AAA group for age, sex, hypertension, diabetes mellitus, and hyperlipidaemia. The presence of ACE polymorphism was detected by a polymerase chain reaction using DNA extracted from blood. RESULTS: the distribution of ACE genotypes and allele frequencies in the control and AAA groups was not significantly different. CONCLUSION: the deletion polymorphism in the ACE gene is not a risk factor for AAA.

Aged↗
PubMed1999

Orlistat, a lipase inhibitor, for weight maintenance after conventional dieting: a 1-y study.

BACKGROUND: Long-term maintenance of weight loss remains a therapeutic challenge in obesity treatment. OBJECTIVE: This multicenter, double-blind, placebo-controlled study was designed to test the hypothesis that orlistat, a gastrointestinal lipase inhibitor, is significantly more effective than a placebo in preventing weight regain. DESIGN: Obese subjects who lost > or = 8% of their initial body weight during a 6-mo lead-in of a prescribed hypoenergetic diet (4180-kJ/d deficit) with no adjunctive pharmacotherapy were randomly assigned to receive placebo, 30 mg orlistat, 60 mg orlistat, or 120 mg orlistat 3 times daily for 1 y in combination with a maintenance diet to help prevent weight regain. Of 1313 recruited subjects [body mass index (in kg/m2): 28-43], 729 subjects lost > or =8% of their initial body weight during the 6-mo weight-loss lead-in period and were enrolled in the double-blind phase. RESULTS: After 1 y, subjects treated with 120 mg orlistat 3 times daily regained less weight than did placebo-treated subjects (32.8 +/- 4.5% compared with 58.7 +/- 5.8% regain of lost weight; P < 0.001). Moreover, more subjects in the 120-mg orlistat group than in the placebo group regained < or = 25% of lost weight (47.5% of subjects compared with 29.9%). In addition, orlistat treatment (120 mg 3 times daily) was associated with significantly greater reductions in total and LDL-cholesterol concentrations than was placebo (P < 0.001). CONCLUSION: The use of orlistat during periods of attempted weight maintenance minimizes weight readjustment and facilitates long-term improvement in obesity-related disease risk factors.

Adult↗
PubMed1999

Preparation of lecithin microcapsules by a dilution method using the Wurster process for intraarterial administration in gadolinium neutron capture therapy.

Lecithin microcapsules containing gadolinium (Gd) were designed and prepared as a dosage form for intraarterial administration to accumulate Gd in tumors in neutron capture therapy. The microcapsules were composed of 1) a lactose core, 2) a layer of distearylamide of gadopentetic acid (Gd-DTPA-SAm) and polyvinylpyrrolidone (PVP) with or without soybean lecithin (SL) and 3) a membrane containing SL, cholesterol, stearic acid and PVP at three different compositions. A dilution method using the Wurster process was developed for small-scale preparation. In spite of using only 2 g of Gd-DTPA-SAm each, three types of microcapsules were obtained with a content of 24.9% as Gd-DTPA-SAm (3.66% as Gd) even at 150% coating level. The swelling type of microcapsules (MC-D1) did not release Gd at all for the entire 120 min of the experiment in a 0.9% saline solution. On the other hand, the rapid-erosion type (MC-D2) and the vesicle-dispersing type (MC-D3) released Gd with a lag time. The percent released depended on the coating level and the SL content in the Gd-fixing layer. A large number of droplet-like particles spouted out, and/or tubular vesicles formed with MC-D2 and MC-D3 in the saline solution. These phenomena implied that the water-insoluble Gd-DTPA-SAm would be entrapped in these particles/vesicles. When MC-D2 and MC-D3 were administered to normal rats via the hepatic artery, a Gd-accumulation as high as 70 and 71% of the injected dose was detected in the whole liver 2 h after administration. In addition, biochemical and histological evaluation of the liver after administration indicated that embolization of the microcapsules actually occurred in the blood vessels, and that necrosis induced by ischemia was not serious. These results suggested that administration of these microcapsules might be multiply repeated in order to accumulate the required amount of Gd in tumors.

Animals↗
PubMed1999

[Anesthetic management of patients with malignant pleural effusion undergoing hyperthermic perfusion under thoracoscopy].

Nine patients with malignant pleural effusion due to lung cancer had been scheduled for hyperthermic treatment with warmed distilled water (40 degrees C) under thoracoscopy. This treatment aims to produce adhesion of the lungs to reduce pleural effusion. To evaluate the risk of general anesthesia for patients with lung cancer at the end stage, we examined the problems of perioperative management. Seven out of nine patients were classified into ASA physical status > or = III and seven patients into Hugh Jones > or = III Shapiro's score was > or = 5 in four patients. The average %VC was 60 +/- 16 and % FEV1.0 was 41 +/- 18% (means +/- SE). A double lumen endotracheal tube was inserted and anesthesia was maintained with inhalational anesthetics. In two cases, one-lung ventilation could not be maintained because of severe hypoxemia during hyperthermic perfusion. Hypertension occurred in three cases and hypotension in one by direct heat stimulation of the cardiopulmonary system. Although their preoperative risk was poor, there were no major complications and the quality of life was improved. We stress that careful anesthetic management is important for avoiding hypoxemia and hemodynamic instability during this treatment.

Aged↗
PubMed1998

Protein release from collagen matrices.

The effective delivery of protein drugs is an important research subject in the field of pharmacology, and to prolong the effect of protein drugs, many studies are being conducted to control the release of proteins from various carrier materials. Collagen is one of the most useful candidates for this purpose, and many studies have been reported; pharmaceutical formulations containing collagen in gel, film and sponge form are used to incorporate low-molecular-weight compounds such as antibiotics and carcinostatics, and the release of these compounds is controlled by the concentration of the gel as well as the shape and degree of crosslinking of the matrix. However, it is still difficult to retain protein drugs in the collagen. In this article, we report on the controlled release of protein drugs using collagen which exhibits good biocompatibility as a carrier, focusing on a new drug delivery system, the Minipellet, which we have developed.

Journal Article↗
PubMed1998

Local application of basic fibroblast growth factor minipellet induces the healing of segmental bony defects in rabbits.

Fibroblast growth factor (FGF) has been reported to increase the volume of callus in a fracture model of rats. There are, however, no reports of successful repair of segmental bony defects by application of an FGF solution. In this study, the effects of basic FGF on the repair of segmental bony defects in the rabbit femur were examined. Minipellet, a new drug delivery system using atelocollagen, was employed to ensure effective delivery of FGF. Segmental bony defects (10 mm in length) were created in the right femurs of 19 rabbits. In pilot studies, no defects of this size healed spontaneously within 6 weeks. Bones were stabilized with miniexternal fixators. Minipellets containing basic FGF were implanted between fragments so as to bridge the two fragments. The healing processes were monitored radiographically and studied histologically. In rabbits in which FGF was added to the defect site at doses of 1.4 microgram or higher, approximately 90% of the defects were filled with new bone and cartilage within 6 weeks after minipellet implantation. In rabbits receiving placebo minipellets, however, approximately 15% of the defects were filled by callus within 6 weeks. Furthermore, this callus did not change into mature bone. An injection of 2 microgram of FGF solution to bony defects had no effect on the repair of segmental bony defects. These findings suggest that FGF plays a role in the production of adequate volumes of callus particularly in the initial stages of fracture healing and that sustained local release enables FGF to be effective at a low dose. In summary, large segmental bony defects healed after insertion of low-dose FGF minipellets. An adequate dose of FGF and an appropriate delivery system are required for successful healing of large bony defects. These findings imply the potential value of FGF minipellets in clinical practice.

Animals↗
PubMed1998

Arterial reconstruction: justified for patients with intermittent claudication?

The objective of this study was to evaluate the effects of arterial reconstruction in patients with intermittent claudication. A total of 243 patients (305 limbs) underwent lower extremity vascular reconstruction at our institution from 1979 to 1995. They were assessed by physical examination, pulse volume recordings, segmental pressure, Duplex ultrasonography, and intravenous subtraction arteriography to evaluate the effects of arterial reconstruction. Surviving patients (220 limbs) were enrolled for evaluation of outcome during the follow-up period. There were 59 deaths during the follow-up period. The cumulative life-table 5-year patency rates were 90% +/- 3%, 73% +/- 6%, and 74% +/- 10% for aortoiliac, infrainguinal, and aortofemorodistal arterial reconstructions, respectively. Among 129 repairs in the aortoiliac region, Fontaine stages I, II, and III were found in 109 limbs (84.5%), 17 limbs (13.2%), and 2 limbs (1.5%), respectively. There was one (0.7%) minor amputation. There was Fontaine stage I in 50 limbs (76.9%), Fontaine stage II in 14 limbs (21.5%), and Fontaine stage III in 1 limb (1.5%) for repairs in the infrainguinal region. Among the 26 aortofemorodistal repairs, there was Fontaine stage I in 21 limbs (81%) and Fontaine stage II in 5 limbs (19%). There was a statistically significantly higher incidence of Fontaine stage I than Fontaine stage II or III in aortofemoral, infrainguinal, and aortofemorodistal arterial reconstructions (p < 0.0001). Arterial reconstruction for patients at Fontaine stage II offered benefits and improved quality of life at follow-up. Arterial reconstruction for patients at Fontaine stage II offers benefits and improved quality of life at follow-up. It was concluded that the significant improvement in quality of life after arterial reconstruction warrants continued use of the procedure in patients with intermittent claudication.

Adult↗
PubMed1998

Detection of type III collagen fragments in specimens of abdominal aortic aneurysms.

The purpose of this study was to analyze the collagens in aortic aneurysm walls and to investigate the mechanism of the formation of calcified abdominal aortic aneurysms (AAAs). Collagens were extracted from human aneurysmal aortic walls obtained during surgery, and from human nonaneurysmal aortic walls obtained at autopsy, using pepsin-acetic acid digestion. Electrophoresis and immunoblotting were performed. Type III collagen was found to be reduced in the arteriosclerotic aneurysmal aortic walls. The alpha1 chain of type II collagen/alpha1 chain of type I collagen ratio was 0.35+/-0.11 in the aortic aneurysms and 0.68+/-0.11 in the nonaneurysmal aortic walls (P=0.0111). All the calcified aneurysms were associated with type III collagen fragments having molecular mass of approximately 70 kDa and 30 kDa as estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Thus, we concluded that AAAs with calcification may be caused by an abnormal degradation of type III collagen.

Aortic Aneurysm, Abdominal↗
PubMed1998

The lack of type III collagen in a patient with aneurysms and an aortic dissection.

We analyzed 79 consecutive patients with aneurysms and found a patient who lacked type III collagen. Collagen was extracted from the skin, and the lack of type III collagen was determined by means of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Only 1 of the 79 patients was found to lack type III collagen. This patient was a 55-year-old man who had sustained an abdominal aortic aneurysm and aortic dissection. He did not show any of the typical clinical symptoms of Ehlers-Danlos syndrome type IV, such as hyperextensible skin and joints. He had none of the usual risk factors nor any clear family history of the syndrome. Furthermore, his collagen fibrils demonstrated a homogeneous appearance. This case may represent a new form of type III collagen deficiency.

Aortic Dissection↗
PubMed1998

Loss of heterozygosity of NF1 gene in juvenile chronic myelogenous leukemia with neurofibromatosis type 1.

To investigate a genetic relation between juvenile chronic myelogenous leukemia (JCML) and neurofibromatosis type 1 (NF-1), we analyzed the NF1 gene in the leukemic cells of a JCML patient with NF-1. We found a point mutation in exon 29 of one allele and a deletion of the other normal allele in the leukemic cells. The point mutation is considered a germline mutation because it was also detected in fibroblasts obtained from the bone marrow of the patient and the peripheral blood mononuclear cells from a sibling. A loss of heterozygosity of NF1 gene may contribute to the progression of leukemia in NF-1 patients.

Alleles↗
PubMed1998

Distribution of nerve growth factor in cat brains following topical application of solution or Minipellet.

The distribution of nerve growth factor (NGF) was studied after topical application of NGF solution or NGF Minipellet into the caudate nucleus of cat brains. Each aliquot of NGF solution or a piece of NGF Minipellet contains 200 micrograms of mouse 2.5S beta-NGF. The concentrations of NGF in various areas of the brain were determined by enzyme-linked immunosolvent assay (ELISA). The tissue concentrations of NGF were very high at 6 h after injection of NGF solution (124.0 +/- 2.46 to 2144.0 +/- 16.03 ng g-1), but quickly decreased on day 1. The tissue concentrations of NGF were low at 6 h after implantation of NGF Minipellet, but were considerably increased on day 1 (11.22 +/- 3.36 to 72.04 +/- 20.45 ng g-1), and slowly decreased during the following 6 to 14 days. The present study demonstrates the temporal and spatial profiles of NGF distribution in the brain of middle-sized animals after topical application. Injection of NGF solution resulted in abrupt, but very transient, elevation of tissue NGF. Implantation of NGF Minipellet maintained the tissue NGF at biologically effective levels for 6 to 14 days.

Administration, Topical↗