The antiproliferative action of a melphalan hexapeptide with collagenase-cleavable site

Purpose: The objective of the present study was to examine the relevance of collagenase in the antitumor action of a melphalan peptide (MHP) with a collagenase-cleavable sequence. The question was addressed as to whether collagenase may act as an activator or a target in the antiproliferative mechanism of MHP. Methods: Melphalan was inserted into peptides representing the sequence Pro-Gln-Gly-Ile-Ala.Gly of the collagenase-cleavable site in collagens. Changes in growth and collagenase IV activities of HT-1080, HT-29, HT-168, and MCF-7 cell cultures were investigated. Results: The present investigations provide data indicating that Pro-Gln-Gly-Ile-Mel-Gly (melphalan hexapeptide, MHP) is a substrate for both bacterial and 72-kDa type IV collagenases and that in this way it can generate Ile-Mel-Gly (melphalan tripeptide, MTP) of higher cytotoxic potency. Indeed, the formation of MTP was detected in the conditioned medium of HT-1080, a collagenase IV-producing human fibrosarcoma. In a comparison of equimolar concentrations of melphalan and its two peptide derivatives (MHP and MTP), superior antiproliferative action of MTP was seen in HT-29, HT-1080, and HT-168 tumor cell cultures. However, the relatively modest cytostatic actions of MHP were increased when bacterial collagenase was added to the cell cultures. After melphalan treatment, reduced levels of both 92 and 72-kDa type IV collagenases were seen in the HT-1080 cell cultures. However, the reduction of collagenase activity and the cell counts did not run parallel in the MTP- or MHP-treated cultures; indeed, collagenase activity related to cell numbers showed an elevated level. Conclusions: As the conversion of MHP to the more toxic MTP was detected in the presence of collagenases, it is possible that collagenase-directed activation of prodrugs may be a promising approach for the development of more selective cytostatic drugs against malignant tumors with high collagenase activities. Received: 6 October 1996 / Accepted: 22 July 1997     

Pharmacokinetics and safety of intravitreally delivered etanercept

Background The anti-inflammatory drug etanercept may be an effective therapeutic agent in diabetic retinopathy. In order to further evaluate its potential, the pharmacokinetics and safety of this drug after intravitreal delivery were investigated.Methods After intravitreal administration of etanercept in rabbits, clinical examination, electroretinography (ERG), visually evoked potentials (VEP) and histology were evaluated. The pharmacokinetics and distribution of etanercept were analyzed using fluorescence-coupled protein at 0, 2, 4, and 8 weeks after injection in vitreous, retina, and choroid.Results No adverse effects and signs of toxicity were found. Etanercept showed peak concentrations after 4 weeks in the retina and choroid.Conclusions Intravitreally delivered etanercept is safe and results in high concentrations in the retina and choroid over a long period of time.     

Effectiveness of Scapular Stabilization Versus Non-Stabilization Stretching on Shoulder Range of Motion,a Randomized Clinical Trial

BackgroundPrevious research has demonstrated the benefits of both stabilization and non-stabilization of the scapula during stretching in individuals with posterior shoulder tightness, but limited evidence exists in patients with shoulder pain.Hypothesis/PurposeThe aim of this study was to determine the effect of stabilized scapular stretching on patients with shoulder pain. The primary hypothesis of this study is that stabilized scapular stretching will improve glenohumeral motion and pain compared to non-stabilized stretch program. A secondary hypothesis of this study is that stabilized scapular stretching will produce greater improvement in function compared to the non-stabilized stretching program.Study DesignRandomized Clinical TrialMethodsSixteen patients with sub-acromial pain associated with tendinopathy and associated pathologies presenting to physical therapy were randomized into two groups (stabilized or non-stabilized scapular stretching). Baseline pain and range of motion were measured prior to and following each treatment session for three visits that occurred over the course five to seventeen days depending on the patients availability. The dependent measurements were stabilized horizontal adduction, stabilized internal rotation, stabilized shoulder flexion, non-stabilized shoulder flexion, and current pain level.ResultsPatients in the scapular stabilization stretching group increased horizontal adduction 40° (CI₉₅ 31, 48°) compared to the non-stabilization stretching group increase of 8° (CI₉₅ 0, 17°) over the course of the three treatments (p<0.001). Similarly, the stabilized stretching group increased internal rotation 48° (CI₉₅ 26, 69°) compared to the non-stabilized stretching group increase of 26° (CI₉₅ 4, 48°) (p=0.001). Pain decreased in the stabilized stretching group by 1.4 points (CI₉₅ -0.4, 3.2) but increased slightly in non-stabilized group by -0.5 points (CI₉₅ -2.3, 1.3) which was not a clinically meaningful change. (p=0.03)ConclusionStabilized scapular stretching was more effective than non-stabilized stretching at gaining shoulder mobility in patients with shoulder pain. Benefits were immediate and sustained between treatment sessions. Stretching interventions improved range of motion but had limited effect on shoulder pain.Level of Evidence2     

Endovascular treatment of traumatic aortic rupture using iliac extension stent-grafts in patients with small aortic diameters

Open in a separate window OBJECTIVESTo evaluate outcomes after thoracic endovascular aortic repair in young patients sustaining traumatic blunt aortic injury (BAI) using iliac extension stent-grafts because of small aortic diameters measuring <24 mm.METHODSRetrospective analysis regarding clinical presentation, trauma management, endovascular techniques and outcome of patients with a small descending aorta involving an iliac extension stent-graft to treat traumatic BAI.RESULTSAmong 48 patients who suffered a BAI and underwent thoracic endovascular aortic repair, 7 received iliac extension stent-grafts. They were 27.4/[standard deviation (SD): −13.1] years old and 6 out of 7 were male. The iliac extension stent-graft was used as distal stent-graft, and a thoracic stent-graft was used in most patients as proximal extension. We achieved overall technical success in all patients during a procedure lasting 92.6 (SD: 54.9) min. One patient died 2 days after the endovascular procedure of hypoxic brain injury, and another died after 17 days of liver failure. That patient had also suffered a spinal cord injury following the procedure, as the stent-graft had been deployed in Ishimaru Zone 2, and the carotid to subclavian bypass had to be omitted because of his critical condition. Control computed tomographic angiographs was available in 6 patients after 7.7 (SD: 5.1) days and showed no endoleak. The surviving patients were discharged after 18.4 (SD: 13.4) days.CONCLUSIONSTreating traumatic BAI using iliac extension stent-grafts in young patients with small aortic diameters is feasible. We observed no mortality caused by the BAI or related to endovascular therapy within this small patient cohort.     

Characterization of Healthcare-Associated and Community-Associated Clostridioides difficile Infections among Adults,Canada, 2015–2019

We investigated epidemiologic and molecular characteristics of healthcare-associated (HA) and community-associated (CA) Clostridioides difficile infection (CDI) among adult patients in Canadian Nosocomial Infection Surveillance Program hospitals during 2015–2019. The study encompassed 18,455 CDI cases, 13,735 (74.4%) HA and 4,720 (25.6%) CA. During 2015–2019, HA CDI rates decreased by 23.8%, whereas CA decreased by 18.8%. HA CDI was significantly associated with increased 30-day all-cause mortality as compared with CA CDI (p<0.01). Of 2,506 isolates analyzed, the most common ribotypes (RTs) were RT027, RT106, RT014, and RT020. RT027 was more often associated with CDI-attributable death than was non-RT027, regardless of acquisition type. Overall resistance C. difficile rates were similar for all drugs tested except moxifloxacin. Adult HA and CA CDI rates have declined, coinciding with changes in prevalence of RT027 and RT106. Infection prevention and control and continued national surveillance are integral to clarifying CDI epidemiology, investigation, and control.     

How we make choices and sacrifices in medical education during the COVID-19 pandemic

Abstract

In this commentary, we highlight some of the pressing choices and sacrifices we must make in medical education during the COVID-19 pandemic.