Effect of topical basic fibroblast growth factor on the healing of chronic diabetic neuropathic ulcer of the foot. A pilot,
randomized, double-blind, placebo-controlled study.
J L Richard ,
C ...Parer-Richard ,
J P Daures ,
S Clouet ,
D Vannereau ,
J Bringer ,
M Rodier ,
C Jacob and
M Comte-Bardonnet
Department of Dietetics and Diabetology, Centre Medical, Le Grau du Roi, France.
Abstract
OBJECTIVE--To assess the efficacy and safety of topical human recombinant basic fibroblast growth factor (bFGF) on the healing
of diabetic neurotrophic foot ulcers. RESEARCH DESIGN AND METHODS--Seventeen diabetic patients suffering from chronic neuropathic
ulcer of the plantar surface of the foot entered a pilot, randomized, double-blind study comparing local application of bFGF
with placebo. Main inclusion criteria were a typical neuropathic ulcer of Wagner grade I-III, more than 0.5 cm in the largest
diameter, with an abnormally high vibration perception threshold in the absence of significant peripheral vascular disease
or wound infection. bFGF or placebo was applied daily during the 6 weeks as inpatients then twice a week for 12 weeks. Evolution
of ulcer size was assessed through weekly clinical examination and computerized photographs. RESULTS--In the bFGF group, three
of nine ulcers healed compared with five of eight in the placebo group (NS). The weekly reduction in ulcer perimeter and area
was identical in both groups, as was the rate of linear advance from entry to the 6th week of treatment (bFGF: 0.053 +/- 0.048
mm vs. placebo: 0.116 +/- 1.129 mm): the same result was obtained at the 11th week. Moreover, percent healed area at the end
of the study did not differ significantly. No side effects were observed during bFGF application. CONCLUSIONS--Topical application
of bFGF has no advantage over placebo for healing chronic neuropathic diabetic ulcer of the foot. Because diabetes causes
significant wound-healing defects, we hypothesized that using a single growth factor might be insufficient to accelerate wound
closure of diabetic ulcers.
Prior to a clinical trial in humans, we studied the effect and pharmacological distribution of recombinant human basic fibroblast growth-factor (Rh-bFGF) in vivo. Healing experiments on ...de-epithelialized rabbits corneas (n = 24 animals) compared the efficacy of three bFGF doses to controls and revealed a significantly increased healing rate for both 200 ng and 500 ng per application Rh-bFGF treatment groups compared to the control groups. To assess possible side effects of Rh-bFGF (500 ng topically applied for up to 7 days, twice daily), ten rabbits were involved in a model of an anterior keratectomy wound (performed with Draeger's roto-keratome to a depth of 0.15 mm). Light microscopy of thin sections of treated corneas showed an increased fibrogenesis in the anterior stroma with a more pronounced activation of keratocytes. No evidence for abnormal neovascularization or inflammation was observed when compared to control corneas. Ocular penetration and systemic distribution of topically applied labelled 125I FGF was assessed in three models (iodine vapour epithelial burn, anterior keratectomy and penetrating autokeratoplasty) in 24 rabbits. No intraocular penetration of bFGF occurred as shown by direct gamma counting. Macroautoradiography showed a selective labelling of epithelial basement membrane when denuded and intact, as previously described. Evidence for systemic absorption of breakdown products was confirmed by heparin-sepharose chromatography of blood and urine samples. Under these conditions, we suggest that topical Rh-bFGF promotes corneal wound healing without morphological adverse reaction or intraocular and systemic penetration.
We have previously shown that bovine, human placenta extracted and recombinant human basic Fibroblast Growth Factor (bFGF) are effective in enhancing corneal epithelial wound healing in vivo. In the ...present study, we investigated the effect of rh-bFGF on the regeneration of injured rabbit endothelium. A standardized wound was created by scraping of endothelial cells with a special device within the boundaries of a central epithelial trephine mark of 7 mm in diameter. A single dose of 1.5 μg rh-bFGF was injected into the anterior chamber immediately after wounding, while control eyes received the vehicle only (n = 27). Functional recovery and wound closure rates were assessed by means of ultrasonic pachymetry, corneal button wet weight, endothelial vital staining as well as direct computer assisted surface analysis of Janus green stained corneal buttons. Measurements were carried out 1, 2, 4, and 7 days after injury. Morphological evaluation and cell counts at D4 and D7 were also performed. Significant stimulation of endothelial regeneration in rh-bFGF treated eyes, was observed with all methodological approaches. These results demonstrate the effectiveness of rh-bFGF in enhancing experimental corneal endothelial wound healing and advocate for a possible clinical application of this growth factor in order to preserve endothelial cell function or to promote healing of this important monolayer in case of disease or injury.
Rare loss-of-function mutations in the calcium-sensing receptor (Casr) gene lead to decreased urinary calcium excretion in the context of parathyroid hormone (PTH)-dependent hypercalcemia, but the ...role of Casr in the kidney is unknown. Using animals expressing Cre recombinase driven by the Six2 promoter, we generated mice that appeared grossly normal but had undetectable levels of Casr mRNA and protein in the kidney. Baseline serum calcium, phosphorus, magnesium, and PTH levels were similar to control mice. When challenged with dietary calcium supplementation, however, these mice had significantly lower urinary calcium excretion than controls (urinary calcium to creatinine, 0.31±0.03 versus 0.63±0.14; P=0.001). Western blot analysis on whole-kidney lysates suggested an approximately four-fold increase in activated Na(+)-K(+)-2Cl(-) cotransporter (NKCC2). In addition, experimental animals exhibited significant downregulation of Claudin14, a negative regulator of paracellular cation permeability in the thick ascending limb, and small but significant upregulation of Claudin16, a positive regulator of paracellular cation permeability. Taken together, these data suggest that renal Casr regulates calcium reabsorption in the thick ascending limb, independent of any change in PTH, by increasing the lumen-positive driving force for paracellular Ca(2+) transport.
ABSTRACT
Chemical characterization of cryptotephra is critical for temporally linking archaeological sites. Here, we describe cryptotephra investigations of two Middle–Upper Paleolithic sites from ...north‐west Italy, Arma Veirana and Riparo Bombrini. Cryptotephra are present as small (<100 µm) rhyolitic glass shards at both sites, with geochemical signatures rare for volcanoes in the Mediterranean region. Two chemically distinct shard populations are present at Arma Veirana (P1 and P2). P1 is a high silica rhyolite (>75 wt.%) with low FeO (<1 wt.%) and a K2O/Na2O > 1 and P2 is also a high silica rhyolite (>75 wt.%) but with higher FeO (2.33–2.65 wt.%). Shards at Riparo Bombrini (P3) are of the same composition as P1 shards at Arma Veirana, providing a distinct link between deposits at both sites. Geochemical characteristics suggest three possible sources for P1 and P3: eruptions from Lipari Island (56–37.7 ka) in Italy, the Acigöl volcanic field (200–20 ka) in Turkey and the Miocene Kirka‐Phrigian caldera (18 Ma) in Turkey. Eruptions from Lipari Island are the most likely source for P1,3 cryptotephra. This study highlights how cryptotephra can benefit archaeology, by providing a direct link between Arma Veirana and Riparo Bombrini as well as other deposits throughout the Mediterranean.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The anthracyclines are a family of natural products isolated from soil bacteria with over 2000 chemical representatives. Since their discovery seventy years ago by Waksman and co-workers, ...anthracyclines have become one of the best-characterized anticancer chemotherapies in clinical use. The anthracyclines exhibit broad-spectrum antineoplastic activity for the treatment of a variety of solid and liquid tumors, however, their clinical use is limited by their dose-limiting cardiotoxicity. In this review article, we discuss the toxicity of the anthracyclines on several organ systems, including new insights into doxorubicin-induced cardiotoxicity. In addition, we discuss new medicinal chemistry developments in the biosynthesis of new anthracycline analogs and the synthesis of new anthracycline analogs with diminished cardiotoxicity. Lastly, we review new studies that describe the repurposing of the anthracyclines, or “upcycling” of the anthracyclines, as anti-infective agents, or drugs for niche indications. Altogether, the anthracyclines remain a mainstay in the clinic with a potential new “lease on life” due to deeper insight into the mechanism underlying their cardiotoxicity and new developments into potential new clinical indications for their use.
Keywords: Anthracycline, chemotherapy, toxicology, medicinal chemistry, biosynthesis.
•A brief review of new mechanisms underpinning anthracycline toxicity•Updates on anthracycline structure-activity-relationships (SAR) regarding cardiotoxicity and antiproliferative activity•Discussion about new indications for anthracyclines as anti-infectives
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A 40-year-old man, newly diagnosed with cardiac sarcoidosis (CS) presented with symptomatic ventricular tachycardia three days after starting steroid-based immunosuppressive therapy (IT). There was ...no clear guideline indication for implantable cardioverter-defibrillator (ICD) before the initiation of IT. Shortly after ICD implantation and the initiation of anti-arrhythmic drugs, recurring ventricular arrhythmias required titration of the anti-arrhythmic drug therapy. One-year follow-up assessment showed no significant arrhythmias and complete PET scan FDG uptake suppression. This case, along with recent publications, suggests transient pro-arrhythmic effects of steroids in patients with CS, which are not appropriately addressed in the current guidelines. We believe ICD implantation should be considered in clinically manifest CS before initiating IT, particularly in cases with heterogeneous and/or extensive FDG uptake on PET scans.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
Aims
To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification.
Methods and results
A multicentre, international, ...retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children {55.7% boys, 40.3% probands, median age: 8.0 interquartile range (IQR) 9.5 years} from 350 families were included; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiac conduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolated Brugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a median follow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients. Patients whose mutation localized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation, age ≤1 year at diagnosis in probands and age ≤1 year at diagnosis in non-probands were independent predictors of CE.
Conclusion
In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the most prevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent risk factors were identified, including age ≤1 year at diagnosis, compound mutation, and mutation with both gain- and loss-of-function.
Background and Objectives
Blood transfusion is performed daily in hospitals. Gaps exist between transfusion guidelines and day‐to‐day clinical care. These gaps are prevalent in resource‐limited ...settings due to scarce continuing medical education. Transfusion Camp Rwanda aims to bridge this gap by (1) delivering context‐appropriate up‐to‐date education, (2) teaching participants how to independently deliver a case‐based curriculum and (3) identifying strategies to promote change in transfusion practice in Rwanda.
Materials and Methods
In May 2023, a multidisciplinary team from Canada and Rwanda carried out a Transfusion Camp train‐the‐trainer workshop for clinicians from all five provinces in Rwanda. Participants attended in‐person lectures, seminars and workshop group discussions on the implementation of the Rwanda National Directives on Rational Use of Blood and Blood Components. Course feedback was based on the Kirkpatrick Model of Training and Evaluation.
Results
Fifty‐one physicians and laboratory technicians participated in the course. Confidence in caring for patients based on transfusion guidelines was self‐rated as ‘excellent’ by 23% of participants before and 77% after, while 84% reported they planned to teach Transfusion Camp to others and 100% responded that they will apply course content to clinical practice. Workshop groups recommended strategies to improve transfusion medicine practice in Rwanda in four domains: Communication, Institutional Approval, Practice Audits and Education.
Conclusion
Transfusion medicine education in Rwanda using a train‐the‐trainer approach was well‐received by participants and allowed for a more detailed understanding of the local medical and educational environment. These observations can inform the further expansion of the Transfusion Camp Rwanda project.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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