Biomedical subjects
Publications and source records attributed to D Kessel.
External iliac stenosis due to endofibrosis is a rare condition that predominantly affects top level cyclists. Short term symptomatic relief is reported in an Olympian after percutaneous transluminal angioplasty, which was performed to allow the patient to return to training without delay.
Ursodeoxycholic acid (UDCA) protects cells from the apoptotic effects of hydrophobic bile acids and some other cytotoxic agents. We observed the opposite result when assessing the effects of UDCA on the apoptotic response to mitochondrial photodamage induced by photodynamic therapy (PDT). Two photosensitizers with predominantly mitochondrial specificity were used: a porphycene we have designated CPO; and the tin etiopurpurin SnET2. UDCA potentiated the loss of mitochondrial potential, release of cytochrome c into the cytosol, activation of caspase-3, and apoptotic cell death after irradiation of photosensitized murine leukemia L1210 or hepatoma 1c1c7 cells. These effects were not observed when UDCA was added after irradiation. Glyco-UDCA and tauro-UDCA, conjugated forms of UDCA that are formed in vivo, were as effective as UDCA in promoting PDT phototoxicity. Because UDCA does not act by enhancing intracellular accumulation of the photosensitizing agents used in this study, we propose that the mode of action of UDCA involves the sensitization of mitochondrial membranes to photodamage. UDCA is used currently in gastroenterology for several indications. The drug may offer a means for promoting the efficacy of PDT with minimal adverse effects.
Exposure of murine leukemia L1210 cells to the antitumor antibiotic cryptophycin 52 (C52) led to cell-cycle arrest at the prometaphase/metaphase interface within 18 h, but apoptotic nuclei did not appear until 36 h later. To determine whether accumulation of cells in early metaphase might have delayed the apoptotic process, cells were treated with C52 for 18 h and a photodynamic process was used to initiate the release of mitochondrial cytochrome c. Apoptosis was observed within 60 min, indicating that the slow apoptotic response was not caused by an impaired ability of genomic DNA to undergo endonucleosomal cleavage during cell-cycle arrest induced by cryptophycin 52.
BACKGROUND: Peripheral arterial thrombolysis has become established as a useful adjunct in the management of peripheral arterial ischaemia. Much has been learnt about indications, risks and benefits using this technique, although data from randomised controlled studies is not extensive. The optimal initial management of the acutely ischaemic leg needs to be determined. OBJECTIVES: To determine if surgery or thrombolysis is the preferred option in the initial treatment of acute limb ischaemia. SEARCH STRATEGY: The search strategy was that adopted by the Cochrane Review Group on Peripheral Vascular Diseases. Additionally, reference lists of papers resulting from this search were reviewed. SELECTION CRITERIA: All randomised studies comparing thrombolysis and surgery in the management of acute limb ischaemia. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data were extracted independently by all three reviewers. MAIN RESULTS: Patients with acute lesions of less than seven days duration had a significantly increased survival at one year for patients having thrombolysis, compared to those undergoing initial surgery [84% v 58%, p=0.01; Odds ratio (95% CI) 0.28 (0.13,0.63)] largely associated with a reduced level of in-hospital cardio-pulmonary complications (Ouriel 1994). Lesions less than 14 days duration fared better with initial lysis with a reduced amputation and reduced death rate at six months [15.3% v 37.5%; p=0.001; Odds ratio (95%CI) 0.29 (0.12,0.72)] (STILE 1994), compared to initial surgery. Analysis of the same trial at one year however revealed that native vessel thromboses had a more favourable outcome with initial surgery, largely due to continuing ischaemia in the lytic group [64% v 35%; p<0.0001; Odds ratio (95%CI) 3.26(1.96,5.52)] (Weaver 1996). Bypass graft thromboses less than 14 days old treated with initial thrombolysis were shown to have a reduced amputation rate (15% v 47%; p=0.05). However, overall, one year results revealed that thrombolysis of thrombosed grafts was associated with a higher level of continued ischaemia [73% v 50%; P=0.010; Odds ratio (95%CI) 2.72(1.27,5.80)] (Comerota 1996). REVIEWER'S CONCLUSIONS: A universal initial treatment with either surgery or thrombolysis cannot be advocated on the available evidence. There is no overall difference in limb salvage or death at one year between initial surgery and initial thrombolysis. Thrombolysis may however be associated with a higher risk of ongoing limb ischaemia, and a higher overall risk of haemorrhagic complications including stroke. The higher risk of complications needs to be balanced against the risks of surgery in the individual patient.
Photodynamic therapy (PDT) is a form of cancer treatment based on the selective accumulation of a photosensitizer (by exogenous or endogenous means) in neoplastic tissue. Subsequent activation of the photosensitizer by a specific wavelength of light results in tumor cell death. Activation of a photosensitizer to the appropriate energy state results in the production of singlet oxygen, a powerful oxidizing agent. PDT can kill cells by three mechanisms: direct cell death by photooxidation, apoptosis, or as a consequence of vascular shutdown. The toxicity of PDT is site specific and dependent on the organ being irradiated and the selectivity of the photosensitizer for target tissue over normal tissue. However, there are also reactions related to the sensitizer per se that are independent of those related to the treatment site. Such reactions include cutaneous photosensitization, nausea, vomiting, hypotension, and altered liver 'function' tests. Excitation of photosensitizer by an incident photon produces reemission of a fluorescent photon, which can be used to detect a tumor that is not ordinarily evident. The major limiting factor in using PDT is the depth of tumor kill. The majority of clinical experience involving PDT of the gastrointestinal tract involves patients who are considered to be poor operative risks, and reported follow-ups after treatment are not only limited but also variable.
PURPOSE: To investigate the suitability of lutetium texaphyrin (lu-tex) as a fluorescence imaging agent in the delineation of retinal vascular and choroidal vascular diseases. The utilization of an efficient fluorescent molecule that is also a photosensitizer represents a unique opportunity to couple diagnosis and therapy. METHODS: Fundus fluorescence angiography comparing lu-tex (motexafin lutetium, Optrin, Pharmacyclics Inc, Sunnyvale, California) with the conventional angiographic dyes, sodium fluorescein, and indocynanine green (ICG), was performed on the eyes of normal and laser-injured New Zealand white rabbits. Plasma pharmacokinetic data and plasma protein binding were assessed in addition to light microscopy of the retina in both imaged and laser-injured eyes. RESULTS: Normal retinal and choroidal vasculature was well delineated by lu-tex angiography. Experimentally induced choroidal and retinal vascular lesions were enhanced by lu-tex and demonstrated different staining patterns than fluorescein or ICG, particularly at the margins of the lesions. Lu-tex cleared rapidly from the plasma, with 39.7% bound to the high-density lipoprotein (HDL) fraction while 15.8% was bound to the low-density lipoprotein (LDL) fraction. No evidence of retinal toxicity after dye administration was observed by either ophthalmoscopy and fundus photography or by light microscopy. CONCLUSION: Lu-tex angiography is a potentially valuable method for retinal vascular and choroidal vascular evaluation, and it has advantages over fluorescein and ICG angiography. The same agent could conceivably be used for both the identification of abnormal vasculature and subsequent photodynamic treatment.
Explore the source record for details and available documents.
PURPOSE: To present a case of symptomatic mesenteric bypass graft stenosis treated with Palmaz stent implantation. METHODS AND RESULTS: A 65-year-old man with a history of mesenteric ischemia and superior mesenteric artery (SMA) occlusion presented with recurrent symptoms 3 years after Dacron graft revision surgery for occlusion of a venous aorto-SMA bypass graft. Graft thrombectomy revealed a tortuous segment of narrowed graft proximally, and a Palmaz stent was deployed across the defect. Adequate flow was restored through the conduit, and the patient has remained asymptomatic for 2 years. CONCLUSIONS: Mesenteric ischemia is a rare and potentially fatal condition requiring major vascular intervention. Revision surgery may be avoided by angioplasty and stent insertion across flow-limiting stenoses, even in prosthetic grafts.
The acetoxymethyl ester of chlorin e6 (CAME) was initially designed to be a hydrophobic photosensitizing agent that would be recognized by an endocytic pathway and initially accumulated in lysosomes. This was expected to lead to hydrolysis of the ester groups, followed by redistribution of the free chlorin to other subcellular sites. In this study, we examined the patterns of localization of CAME and of subsequent photodamage in murine leukemia L1210 cells. The drug was initially localized at intracellular sites, yielding a pattern similar to that obtained with a fluorescent probe for acidic intracellular vesicles and endosomes. A brief (30 min) incubation with 10 microM CAME followed by irradiation led to mitochondrial photodamage and apoptotic cell death. At a higher drug level, or with a longer incubation time, we observed additional photodamage to the plasma membrane and to lysosomes. The higher photodynamic therapy dose led to inhibition of apoptosis, with cell death likely occurring via a necrotic process. Distribution of CAME among the components of human plasma was to albumin > high-density lipoprotein > low-density lipoprotein. These results have implications concerning the likely mechanism of CAME accumulation and subcellular distribution.
Studies with mouse leukemia L1210 cells revealed that selective lysosomal photodamage caused by any of three photosensitizing agents was followed by a gradual loss of the mitochondrial membrane potential (delta psi m), release of cytochrome c into the cytosol, increased DEVDase activity (a measure of levels of caspase-3) and a limited apoptotic response. Similar effects were observed in the murine hepatoma 1c1c7 cell line. Immunofluorescence techniques employing 1c1c7 cells demonstrated the immediate release of the lysosomal enzyme cathepsin B following lysosomal photodamage. These studies suggest that the cytotoxic effects of lysosomal photodamage are initiated by released lysosomal proteases that either directly and/or indirectly activate caspases as a consequence of the induction of mitochondrial damage.
Training of medical staff on minimally invasive surgery (MIS) is an area where new effective training methods are needed. We have studied stent grafting, a type of MIS, which is used to treat abdominal aortic aneurysm. Our analysis revealed that this procedure requires a range of motor, perceptual and cognitive skills. In this paper, we present a training environment that could be used to acquire these skills. Our proposed solution differs from the usual VR solutions by operating within the World Wide Web as an environment for our system. This paper discusses how our solution covers the training skills and presents the results of an appraisal process, which we conducted to evaluate our solution.
Exposure of murine leukemia L1210 cells to the antitumor antibiotic cryptophycin 52 (C52) resulted in a rapid and dose-dependent increase in cell-surface hydrophobicity, as measured with a two-phase partitioning system. This effect was not observed with inactive drug analogs that lacked an epoxy residue. While the C52 has distinctly hydrophobic properties, the drug does not uniformly bind to all proteins. Affinity for human high- and low-density lipoprotein and albumin was demonstrated, but the drug binds only to the albumin fraction of mouse plasma, in spite of the high HDL level in the latter species.
Apoptosis is a cellular death process involving the sequential activation of a series of caspases, endonucleases, and other enzymes. The initiation of apoptosis can be inhibited by overexpression of bcl-2 and certain other members of a related family of proteins. We examined the effects of bcl-2 overexpression on the apoptotic response to photodynamic therapy (PDT), using aluminum phthalocyanine as the photosensitizing agent. In this study, we compared the immortalized human breast epithelial cell line MCF10A with a subline (MCF10A/bcl-2) transfected with the human bcl-2 gene. The latter was approximately 2-fold more sensitive to the phototoxic effects of PDT. At a 50 mJ/cm2 light dose, photodamage to MCF-10A/bcl-2 resulted in a greater loss of the mitochondrial membrane potential (delta(psi)m), enhanced release of mitochondrial cytochrome c, a more rapid and greater activation of caspase-3, and a greater apoptotic response. Western blot analysis revealed that the transfected cell line showed overexpression of both bcl-2 and bax, and that PDT caused selective destruction of bcl-2, leaving bax unaffected. The greater apoptotic response by the transfected line is, therefore, attributed to the higher bax:bcl-2 ratio after photodamage.
OBJECTIVES: To estimate (1) the average number of patients per practitioner in Pediatric Research in Office Settings, the national practice-based research network of the American Academy of Pediatrics; (2) the total number of active patients cared for in the network; and (3) the age-sex distribution of patients seen in pediatric practice. SETTING: Eighty-nine practices in 31 states with 373 Pediatric Research in Office Settings practitioners (59% of Pediatric Research in Office Settings members). METHODS: Practices were asked to enumerate the number of patients visiting the practice during the 2-year period from January 1, 1991, through December 31, 1992. Patients making multiple visits were counted only once, resulting in a patient count rather than a visit count. Age-sex registers were completed using computer billing records or medical record sampling. RESULTS: Study participants cared for 529513 active patients (50.7% male). Each practitioner cared for an average of 1546 patients. The number of patients per practitioner was significantly higher in less-populated areas and in solo practices. Children aged 12 years and younger comprised 81% of the patients seen by Pediatric Research in Office Settings practitioners, and more than half of the children were aged 6 years or younger. Before age 5 years, boys accounted for a slightly, but significantly, higher number of patients, whereas after age 14 years, girls comprised a significantly larger proportion of patients. CONCLUSIONS: The average number of 1546 patients per practitioner derived from these private practice data is in line with health maintenance organization-based estimates. Pediatric practitioners predominantly serve younger children. These data provide the only current national estimates of the size and age-sex distribution of independent pediatric practices, and can help pediatricians and health service researchers plan for the future provision of health care to children.
Explore the source record for details and available documents.
Photodamage to the mitochondria of murine leukemia P388 cells resulted in immediate loss of the mitochondrial membrane potential together with the release of cytochrome c into the cytosol. This was followed by a rapid activation of caspase 3-like proteases, as indicated by a marked rise in DEVDase activity. There was no significant effect on WEHDase or VEIDase activities, suggesting that only the late-stage caspases had been effected. The apoptotic response to mitochondrial photodamage was abolished by the broad-spectrum caspase inhibitor zVAD-fmk, but this did not prevent loss of viability after mitochondrial photodamage. These studies indicate that the release of cytochrome c from photodamaged mitochondria is sufficient to directly initiate a caspase-dependent apoptotic response.
OBJECTIVES: To review our experience of the endovascular management of upper limb embolisation secondary to an ipsilateral proximal arterial lesion. DESIGN: A retrospective study. MATERIALS AND METHODS: Over 3 years, 17 patients presented with blue fingers secondary to an ipsilateral proximal vascular lesion. These have been managed using transluminal angioplasty (14) and arterial stenting (five), combined with embolectomy (two) and anticoagulation (three)/anti-platelet therapy (14). RESULTS: All the patients were treated successfully. There have been no further symptomatic embolic episodes originating from any of the treated lesions, and no surgical amputations. Complications were associated with the use of brachial arteriotomy for vascular access. CONCLUSIONS: Endovascular techniques are safe and effective in the management of upper limb embolic phenomena associated with an ipsilateral proximal focal vascular lesion.
OBJECTIVE: To review current concepts of photodynamic therapy (PDT) applied to the treatment of tumors of the gastrointestinal tract. SUMMARY BACKGROUND DATA: PDT initially involves the uptake or production of a photosensitive compound by tumor cells. Subsequent activation of the photoreactive compound by a specific wavelength of light results in cell death, either directly or as a result of vascular compromise and/or apoptosis. METHODS: The authors selectively review current concepts relating to photosensitization, photoactivation, time of PDT application, tissue selectivity, sites of photodynamic action, PDT effects on normal tissue, limitations of PDT, toxicity of photosensitizers, application of principles of PDT to tumor detection, and current applications of PDT to tumors of the gastrointestinal tract. RESULTS: PDT is clearly effective for small cancers, but it is not yet clear in which cases such treatment is more effective than other currently acceptable approaches. The major side effect of PDT is cutaneous photosensitization. The major limitation of PDT is depth of tumor kill. As data from current and future clinical trials become available, a clearer perspective of where PDT fits in the treatment of cancers will be gained. Many issues regarding pharmacokinetic data of photosensitizers, newer technology involved in light sources, optimal treatment regimens that take advantage of the pharmacophysiology of photoablation, and light dosimetry still require solution. One can foresee application of differing sensitizers and light sources depending on the specific clinical situation. As technologic advances occur, interstitial PDT may have significant application. CONCLUSIONS: PDT has a potentially important role either as a primary or adjuvant mode of treatment of tumors of the gastrointestinal tract.